Vanilloid receptor ligands and their use in treatments

ABSTRACT

Compounds having the general structure  
                 
and compositions containing them, for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.

This application is a division of application Ser. No. 10/445,170, filedMay 20, 2003, which is hereby incorporated by reference.

BACKGROUND

The vanilloid receptor 1 (VR1) is the molecular target of capsaicin, theactive ingredient in hot peppers. Julius et al. reported the molecularcloning of VR1 (Caterina et al., 1997). VR1 is a non-selective cationchannel which is activated or sensitized by a series of differentstimuli including capsaicin and resiniferatoxin (exogenous activators),heat & acid stimulation and products of lipid bilayer metabolism,anandamide (Premkumar et al., 2000, Szabo et al., 2000, Gauldie et al.,2001, Olah et al., 2001) and lipoxygenase metabolites (Hwang et al.,2000). VR1 is highly expressed in primary sensory neurons (Caterina etal., —1997) in rats, mice and humans (Onozawa et al., 2000, Mezey etal., 2000, Helliwell et al., 1998, Cortright et al., 2001). Thesesensory neurons innervate many visceral organs including the dermis,bones, bladder, gastrointestinal tract and lungs; VR1 is also expressedin other neuronal and non-neuronal tissues including but not limited to,CNS nuclei, kidney, stomach and T-cells (Nozawa et al., 2001, Yiangou etal., 2001, Birder et al., 2001). Presumably expression in these variouscells and organs may contribute to their basic properties such ascellular signaling and cell division.

Prior to the molecular cloning of VR1, experimentation with capsaicinindicated the presence of a capsaicin sensitive receptor, which couldincrease the activity of sensory neurons in humans, rats and mice(Holzer, 1991; Dray, 1992, Szallasi and Blumberg 1996, 1999). Theresults of acute activation by capsaicin in humans was pain at injectionsite and in other species increased behavioral sensitivity to sensorystimuli (Szallasi and Blumberg, 1999). Capsaicin application to the skinin humans causes a painful reaction characterized not only by theperception of heat and pain at the site of administration but also by awider area of hyperalgesia and allodynia, two characteristic symptoms ofthe human condition of neuropathic pain (Holzer, 1991). Taken together,it seems likely that increased activity of VR1 plays a significant rolein the establishment and maintenance of pain conditions. Topical orintradermal injection of capsaicin has also been shown to producelocalized vasodilation and edema production (Szallasi and Blumberg 1999,Singh et al., 2001). This evidence indicates that capsaicin through it'sactivation of VR1 can regulate afferent and efferent function of sensorynerves. Sensory nerve involvement in diseases could therefore bemodified by molecules which effect the function of the vanilloidreceptor to increase or decrease the activity of sensory nerves.

VR1 gene knockout mice have been shown to have reduced sensorysensitivity to thermal and acid stimuli (Caterina et al., 2000)). Thissupports the concept that VR1 contributes not only to generation of painresponses (i.e. via thermal, acid or capsaicin stimuli) but also to themaintenance of basal activity of sensory nerves. This evidence agreeswith studies demonstrating capsaicin sensitive nerve involvement indisease. Primary sensory nerves in humans and other species can be madeinactive by continued capsaicin stimulation. This paradigm causesreceptor activation induced desensitization of the primary sensorynerve—such reduction in sensory nerve activity in vivo makes subjectsless sensitive to subsequent painful stimuli. In this regard bothcapsaicin and resinferatoxin (exogenous activators of VR1), producedesensitization and they have been used for many proof of conceptstudies in in vivo models of disease (Holzer, 1991, Dray 1992, Szallasiand Blumberg 1999).

VR1 agonists or antagonists have use as analgesics for the treatment ofpain of various genesis or aetiology, for example acute, inflammatoryand neuropathic pain, dental pain and headache, particularly vascularheadache such as migraine, cluster headache and mixed vascular syndromesas well as non-vascular, tension headache. They are also useful asanti-inflammatory agents for the treatment of inflammatory diseases orconditions, for example the treatment of arthritis and rheumaticdiseases, osteoarthritis, inflammatory bowel disorders, inflammatory eyedisorders (e.g. uvetis), inflammatory or unstable bladder disorders(e.g. cystitis and urinary incontinence), psoriasis and skin complaintswith inflammatory components, as well as other chronic inflammatoryconditions. They are, in particular, useful in the treatment ofinflammatory pain and associated hyperalgesia and allodynia. They arealso useful in the treatment of neuropathic pain and associatedhyperalgesia and allodynia, e.g. trigeminal or herpetic neuralgia,diabetic neuropathy pain, causalgia, sympathetically maintained pain anddeafferentation syndromes such as brachial plexus avulsion. They arealso indicated for the use in the prophylactic or curative treatment ofasthma, of epithelial tissue damage or dysfunction, e.g. spontaneouslesions, of herpes simplex, and in the control of disturbances ofvisceral motility at respiratory, genitourinary, gastrointestinal orvascular e.g. for treating wounds, burns, allergic skin reactions,pruritis and vitiligo, for the prophylactic or curative treatment ofgastrointestinal disorders such as gastric ulceration, duodenal ulcers,inflammatory bowel disease and diarrhea, gastric lesions induced bynecrotising agents, for example ethanol or chemotherapeutic agents, hairgrowth, for the treatment of vasomotor or allergic rhinitis and for thetreatment of bronchial disorders or bladder disorders, such as bladderhyper-reflexia.

BIBLIOGRAPHY

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SUMMARY

The present invention comprises a new class of compounds useful in thetreatment of diseases, such as vanilloid-receptor-mediated diseases andother maladies, such as inflammatory or neuropathic pain and diseasesinvolving sensory nerve function such as asthma, rheumatoid arthritis,osteoarthritis, inflammatory bowel disorders, urinary incontinence,migraine and psoriasis. In particular, the compounds of the inventionare useful for the treatment of acute, inflammatory and neuropathicpain, dental pain, general headache, migraine, cluster headache,mixed-vascular and non-vascular syndromes, tension headache, generalinflammation, arthritis, rheumatic diseases, osteoarthritis,inflammatory bowel disorders, inflammatory eye disorders, inflammatoryor unstable bladder disorders, psoriasis, skin complaints withinflammatory components, chronic inflammatory conditions, inflammatorypain and associated hyperalgesia and allodynia, neuropathic pain andassociated hyperalgesia and allodynia, diabetic neuropathy pain,causalgia, sympathetically maintained pain, deafferentation syndromes,asthma, epithelial tissue damage or dysfunction, herpes simplex,disturbances of visceral motility at respiratory, genitourinary,gastrointestinal or vascular regions, wounds, burns, allergic skinreactions, pruritis, vitiligo, general gastrointestinal disorders,gastric ulceration, duodenal ulcers, diarrhea, gastric lesions inducedby necrotising agents, hair growth, vasomotor or allergic rhinitis,bronchial disorders or bladder disorders. Accordingly, the inventionalso comprises pharmaceutical compositions comprising the compounds,methods for the treatment of vanilloid-receptor-mediated diseases, suchas inflammatory or neuropathic pain, asthma, rheumatoid arthritis,osteoarthritis, inflammatory bowel disorders, urinary incontinence,migraine and psoriasis diseases, using the compounds and compositions ofthe invention, and intermediates and processes useful for thepreparation of the compounds of the invention.

The compounds of the invention are represented by the following generalstructure:

or a pharmaceutically acceptable salt thereof, wherein R¹, R⁴, R^(d), Xand Y are defined below.

The foregoing merely summarizes certain aspects of the invention and isnot intended, nor should it be construed, as limiting the invention inany way. All patents, patent applications and other publications recitedherein are hereby incorporated by reference in their entirety.

DETAILED DESCRIPTION

One aspect of the current invention relates to compounds having thegeneral structure:

or any pharmaceutically-acceptable salt thereof, wherein:

-   -   X is ═N— or ═C(R²)—;    -   Y is ═N— or ═C(R³)—, wherein at least one of X and Y is not ═N—;    -   n is independently, at each instance, 0, 1 or 2.    -   R¹ is    -    or R¹ is a naphthyl substituted by 0, 1, 2 or 3 substituents        independently selected from R⁵; or R¹ is R^(b) substituted by 1,        2 or 3 substituents independently selected from R⁵;    -   R² is, independently, in each instance, R¹⁰, C₁₋₈alkyl        substituted by 0, 1 or 2 substituents selected from R¹⁰,        —(CH₂)_(n)phenyl substituted by 0, 1, 2 or 3 substituents        independently selected from R¹⁰, or a saturated or unsaturated        5- or 6-membered ring heterocycle containing 1, 2 or 3        heteroatoms independently selected from N, O and S, wherein no        more than 2 of the ring members are O or S, wherein the        heterocycle is optionally fused with a phenyl ring, and the        heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3        substituents independently selected from R¹⁰;    -   R³ is, independently, in each instance, H, halo, —NH₂,        —NHC₁₋₃alkyl, —N(C₁₋₃alkyl)C₁₋₃alkyl, or C₁₋₃alkyl; wherein,        when X is ═C(R²)— and Y is ═C(R³)— then at least one of R² and        R³ is other than H;    -   R⁴ is    -    or R⁴ is a saturated or unsaturated 5- or 6-membered ring        heterocycle containing 1, 2 or 3 atoms selected from O, N and S        that is optionally vicinally fused with a saturated or        unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms        selected from O, N and S with the remaining atoms being carbon,        so long as the combination of O and S atoms is not greater than        2, wherein the carbon atoms of the heterocycle and bridge are        substituted by 0, 1, 2 or 3 substituents independently selected        from R^(e), C₁₋₄haloalkyl, halo, nitro, cyano, oxo, —OR^(f),        —S(═O)_(n)R^(e), —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(f),        —OC₂₋₆alkylOR^(f), —OC₁₋₆alkylC(═O)OR^(e), —NR^(a)R^(f),        —NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(f),        —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(c), —C(═O)OR^(e), —OC(═O)R^(e),        —C(═O)NR^(a)R^(f) and —NR^(a)C(═O)R^(e); and unsaturated carbon        atoms may be additionally substituted by ═O; and any available        nitrogen atoms in the heterocycle and bridge are substituted by        H, —C₁₋₆alkylOR^(f), R^(e), —C₁₋₆alkylNR^(a)R^(f),        —C₁₋₃alkylC(═O)OR^(e), —C₁₋₃alkylC(═O)NR^(a)R^(f),        —C₁₋₃alkylOC(═O)R^(e), —C₁₋₃alkylNR^(a)C(═O)R^(c), —C(═O)R^(c)        or —C₁₋₃alkylR^(c); or R⁴ is naphthyl substituted by 1, 2 or 3        substituents independently selected from C₁₋₄haloalkyl, halo,        nitro, cyano, —S(═O)_(n)R^(e), —OC₁₋₄haloalkyl,        —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),        —OC₁₋₆alkylC(═O)OR^(e), —NR^(a)C₁₋₄haloalkyl,        —NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f),        —C(═O)R^(e), —C(═O)OR^(e), —OC(═O)R^(e) and —C(═O)NR^(a)R^(f);        but in no instance is R⁴ 3,5-ditrifluoromethylphenyl or        3-trifluoromethyl-4-fluorophenyl, -phenyl-(C₁₋₈alkyl),        -phenyl-O—(C₁₋₆alkyl), -phenyl-NR^(a)R^(a) or        -phenyl-N(R^(a))C(═O)(C₁₋₆alkyl);    -   R⁵ is independently, at each instance, R^(f), R^(g), halo,        nitro, cyano, —OR^(e), —OR^(g), —OC₂₋₆alkylNR^(a)R^(f),        —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),        —NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,        —CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),        —NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),        —NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),        —S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e),        —OC(═O)NR^(a)R^(f), a phenyl ring substituted with 0, 1, 2, or 3        substituents independently selected from R¹⁰; or R⁵ is a        saturated or unsaturated 5- or 6-membered ring heterocycle        containing 1, 2 or 3 atoms selected from O, N and S, substituted        with 0, 1, 2, or 3 substituents independently selected from R¹⁰;    -   R⁶ is independently, at each instance, H, C₁₋₅alkyl,        C₁₋₄haloalkyl, halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,        —OC₂₋₆alkylNR^(a)R^(b), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a),        —NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆ alkylNR^(a)R^(a) or        —NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a),        —S(C₁₋₆alkyl), a phenyl ring substituted with 1, 2, or 3        substituents independently selected from R¹⁰; or R⁶ is a        saturated or unsaturated 5- or 6-membered ring heterocycle        containing 1, 2 or 3 atoms selected from O, N and S substituted        with 0, 1, 2, or 3 substituents independently selected from R¹⁰;    -   R⁷ is independently, at each instance, H, acyclicC₁₋₈alkyl,        C₁₋₄haloalkyl, halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a),        —NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆        alkylOR^(a), —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a) or        —S(C₁₋₆alkyl); or R⁷ is a saturated or unsaturated 4- or        5-membered ring heterocycle containing a single nitrogen atom,        wherein the ring is substituted with 0, 1 or 2 substituents        independently selected from halo, C₁₋₂haloalkyl and C₁₋₃alkyl;    -   R⁸ is independently, at each instance, H, C₁₋₅alkyl,        C₁₋₄haloalkyl, halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl, —OC₂₋₆        alkylR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a),        —NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a),        —NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a),        —S(C₁₋₆alkyl), a phenyl ring substituted with 1, 2, or 3        substituents independently selected from R¹⁰, or R⁸ is a        saturated or unsaturated 5- or 6-membered ring heterocycle        containing 1, 2 or 3 atoms selected from O, N and S substituted        with 0, 1, 2, or 3 substituents independently selected from R¹⁰;    -   R⁹ is independently, at each instance, R^(f), R^(g), halo,        nitro, cyano, —OR^(e), —OR^(g), —OC₂₋₆alkylNR^(a)R^(f),        —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),        —NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,        —CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),        —NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),        —NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),        —S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e),        —OC(═O)NR^(a)R^(f), a phenyl ring substituted with 0, 1, 2, or 3        substituents independently selected from R¹⁰; or R⁹ is a        saturated or unsaturated 5- or 6-membered ring heterocycle        containing 1, 2 or 3 atoms selected from O, N and S substituted        with 0, 1, 2, or 3 substituents independently selected from R¹⁰;        or R⁹ is a saturated or unsaturated 4- or 5-membered ring        heterocycle containing a single nitrogen atom, wherein the ring        is substituted with 0, 1 or 2 substituents independently        selected from halo, C₁₋₂haloalkyl and C₁₋₃alkyl; wherein at        least one of R⁵, R⁶, R⁷, R⁸ and R⁹ is C₁₋₈alkyl, C₁₋₄haloalkyl,        halo, —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —NR^(a)C₁₋₄haloalkyl,        —NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a),        —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a) or —S(C₁₋₆alkyl);

R¹⁰ is independently, at each instance, selected from H, C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a), —SR^(a),—S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a)—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁰ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁰ isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂(C₈alkyl),—OC₂₋₆ NR^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl),—S(═O)₂(C₁₋₈alkyl), S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);

-   -   R¹¹ is independently, at each instance, selected from H,        C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),        —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),        —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),        —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹¹        is a saturated or unsaturated 5-, 6- or 7-membered monocyclic or        6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 1, 2        or 3 atoms selected from N, O and S, wherein the ring is fused        with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5-,        6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms        selected from N, O and S; wherein the carbon atoms of the ring        are substituted by 0, 1 or 2 oxo groups, wherein the ring is        substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,        C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),        —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —SR^(a), —S(═8)(C₁₋₈alkyl),        —S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a),        —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),        —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)        C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹¹ is        C₄alkyl substituted by 0, 1, 2 or 3 groups selected from        C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),        —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl),        —S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a),        —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),        —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁰        and R¹¹ together are a saturated or unsaturated 3- or 4-atom        bridge containing 1, 2 or 3 atoms selected from O, N and S with        the remaining atoms being carbon, so long as the combination of        O and S atoms is not greater than 2, wherein the bridge is        substituted by 0, 1 or 2 substituents selected from ═O, R^(e),        halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(e),        —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),        —OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(f))S(═O)₂R^(e),        —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(f), —S(═O)R^(e),        —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(f))C(═O)R^(e),        —S(═O)₂N(R^(f))C(═O)OR^(e), —S(═O)₂N(R^(f))C(═O)NR^(a)R^(f),        —NR^(a)R^(f), —N(R^(f))C(═O)R^(e), —N(R^(f))C(═O)OR^(e),        —N(R^(f))C(═O)NR^(a)R^(f), —N(R^(f))C(═NR^(a))NR^(a)R^(f),        —N(R^(f))S(═O)₂R^(e), —N(R^(f))S(═O)₂NR^(a)R^(f),        —NR^(f)C₂₋₆alkylNR^(a)R^(f) and —NR^(f)C₂₋₆alkylOR^(f);    -   R¹² is independently, at each instance, selected from H,        C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),        —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), SR^(a), —S(═O)(C₁₋₈alkyl),        —S(═O)₂(C₁₋₅alkyl), —S(═O)₂NR^(a)R^(a),        —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl),        —N(R^(a))C(═O)O(C₁₋₈alkyl), —N(R^(a))C(═O)NR^(a)R^(a),        —N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂(C₁₋₈alkyl),        —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and        —NR^(a)C₂alkylOR^(a); or R¹² is a saturated or unsaturated 5-,        6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or        11-membered bicyclic ring containing 1, 2 or 3 atoms selected        from N, O and S, wherein the ring is fused with 0 or 1 benzo        groups and 0 or 1 saturated or unsaturated 5-, 6- or 7-membered        heterocyclic ring containing 1, 2 or 3 atoms selected from N, O        and S; wherein the carbon atoms of the ring are substituted by        0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2        or 3 groups selected from C₁₋₈alkyl, C, haloalkyl, halo, cyano,        nitro, —C(═O)(C₁₋₈alkyl), —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a),        —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)(C₁₋₈alkyl),        —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a),        —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a),        —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),        —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂ alkylOR^(a); or R¹² is        C₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected from        C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),        —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a), OC₂        alkylOR^(a), SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C s₈alkyl),        —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),        —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); wherein        if R¹¹ or R¹³ is CF₃, then R¹² is not F; or R¹¹ and R¹² together        are a saturated or unsaturated 3- or 4-atom bridge containing 1,        2 or 3 atoms selected from O, N and S with the remaining atoms        being carbon, so long as the combination of O and S atoms is not        greater than 2, wherein the bridge is substituted by 0, 1 or 2        substituents selected from ═O, R^(e), halo, cyano, nitro,        —C(═O)R^(e), —C(═O)OR^(a)R^(f), —C(═O)NR^(a)R^(f),        —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),        —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(f))S(═O)₂R^(e),        —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(f), —S(═O)R^(e),        —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(f))C(═O)R^(e),        —S(═O)₂N(R^(f))C(═O)OR^(e), —S(═O)₂N(R^(f))C(═O)NR^(a)R^(f),        —NR^(a)R^(f), —N(R^(f))C(═O)R^(e), —N(R^(f))C(═O)OR^(e),        —N(R^(f))C(═O)NR^(a)R^(f), —N(R^(f))C(═NR^(a))NR^(a)R^(f),        —N(R^(f))S(═O)₂R^(e), —N(R^(f))S(═O)₂NR^(a)R^(f)R^(a)R^(f) and        —NR^(f)C₂₋₆alkylOR^(f); wherein when R³ is NH₂, then -R¹¹-R¹²-        is not —C═C—C═N— or any substituted version thereof;

R¹³ is independently, at each instance, selected from H, C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹³ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹³ isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a)NR^(a)R^(a) N(R^(a))C(═O)(C₁₋₈alkyl) —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);

-   -   R¹⁴ is independently, at each instance, selected from H,        C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),        —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a) a,        —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl),        —S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a),        —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),        —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁴        is a saturated or unsaturated 5-, 6- or 7-membered monocyclic or        6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 1, 2        or 3 atoms selected from N, O and S, wherein the ring is fused        with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5-,        6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms        selected from N, O and S; wherein the carbon atoms of the ring        are substituted by 0, 1 or 2 oxo groups, wherein the ring is        substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,        C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),        —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl),        —S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a),        —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),        —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁴        is C₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected from        C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),        —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆        alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),        —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),        —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); wherein        at least one of R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ is other than H;    -   R^(a) is independently, at each instance, H, phenyl, benzyl or        C₁₋₆alkyl;    -   R^(b) is a heterocycle selected from the group of thiophene,        pyrrole, 1,3-oxazole, 1,3-thiazole, 1,3,4-oxadiazole,        1,3,4-thiadiazole, 1,2,3-oxadiazole, 1,2,3-thiadiazole,        1H-1,2,3-triazole, isothiazole, 1,2,4-oxadiazole,        1,2,4-thiadiazole, 1,2,3,4-oxatriazole, 1,2,3,4-thiatriazole,        1H-1,2,3,4-tetraazole, 1,2,3,5-oxatriazole,        1,2,3,5-thiatriazole, furan, imidazol-1-yl, imidazol-4-yl,        1,2,4-triazol-4-yl, 1,2,4-triazol-5-yl, isoxazol-3-yl,        isoxazol-5-yl, pyrazol-3-yl, pyrazol-5-yl, thiolane,        pyrrolidine, tetrahydrofuran, 4,5-dihydrothiophene, 2-pyrroline,        4,5-dihydrofuran, pyridazine, pyrimidine, pyrazine,        1,2,3-triazine, 1,2,4-triazine, 1,2,4-triazine, 1,3,5-triazine,        pyridine, 2H-3,4,5,6-tetrahydropyran, thiane,        1,2-diazaperhydroine, 1,3-diazaperhydroine, piperazine,        1,3-oxazaperhydroine, morpholine, 1,3-thiazaperhydroine,        1,4-thiazaperhydroine, piperidine, 2H-3,4-dihydropyran,        2,3-dihydro-4H-thiin, 1,4,5,6-tetrahydropyridine,        2H-5,6-dihydropyran, 2,3-dihydro-6H-thiin,        1,2,5,6-tetrahydropyridine, 3,4,5,6-tetrahydropyridine,        4H-pyran, 4H-thiin, 1,4-dihydropyridine, 1,4-dithiane,        1,4-dioxane, 1,4-oxathiane, 1,2-oxazolidine, 1,2-thiazolidine,        pyrazolidine, 1,3-oxazolidine, 1,3-thiazolidine, imidazolidine,        1,2,4-oxadiazolidine, 1,3,4-oxadiazolidine,        1,2,4-thiadiazolidine, 1,3,4-thiadiazolidine,        1,2,4-triazolidine, 2-imidazoline, 3-imidazoline, 2-pyrazoline,        4-imidazoline, 2,3-dihydroisothiazole, 4,5-dihydroisoxazole,        4,5-dihydroisothiazole, 2,5-dihydroisoxazole,        2,5-dihydroisothiazole, 2,3-dihydroisoxazole,        4,5-dihydrooxazole, 2,3-dihydrooxazole, 2,5-dihydrooxazole,        4,5-dihydrothiazole, 2,3-dihydrothiazole, 2,5-dihydrothiazole,        1,3,4-oxathiazolidine, 1,4,2-oxathiazolidine,        2,3-dihydro-1H-[1,2,3]triazole, 2,5-dihydro-1H-[1,2,3]triazole,        4,5-dihydro-1H-[1,2,3]triazole, 2,3-dihydro-1H-[1,2,4]triazole,        4,5-dihydro-1H-[1,2,4]triazole, 2,3-dihydro-[1,2,4]oxadiazole,        2,5-dihydro-[1,2,4]oxadiazole, 4,5-dihydro-[1,2,4]thiadiazole,        2,3-dihydro-[1,2,4] thidiazole, 2,5-dihydro-[1,2,4] thiadiazole,        4,5-dihydro-[1,2,4] thiadiazole, 2,5-dihydro-[1,2,4]oxadiazole,        2,3-dihydro-[1,2,4]oxadiazole, 4,5-dihydro-[1,2,4]oxadiazole,        2,5-dihydro-[1,2,4]thiadiazole, 2,3-dihydro-[1,2,4] thiadiazole,        4,5-dihydro-[1,2,4] thiadiazole, 2,3-dihydro-[1,3,4]oxadiazole,        2,3-dihydro-[1,3,4]thiadiazole, [1,4,2]oxathiazole,        [1,3,4]oxathiazole, 1,3,5-triazaperhydroine,        1,2,4-triazaperhydroine, 1,4,2-dithiazaperhydroine,        1,4,2-dioxazaperhydroine, 1,3,5-oxadiazaperhydroine,        1,2,5-oxadiazaperhydroine, 1,3,4-thiadiazaperhydroine,        1,3,5-thiadiazaperhydroine, 1,2,5-thiadiazaperhydroine,        1,3,4-oxadiazaperhydroine, 1,4,3-oxathiazaperhydroine,        1,4,2-oxathiazaperhydroine, 1,4,5,6-tetrahydropyridazine,        1,2,3,4-tetrahydropyridazine, 1,2,3,6-tetrahydropyridazine,        1,2,5,6-tetrahydropyrimidine, 1,2,3,4-tetrahydropyrimidine,        1,4,5,6-tetrahydropyrimidine, 1,2,3,6-tetrahydropyrazine,        1,2,3,4-tetrahydropyrazine, 5,6-dihydro-4H-[1,2]oxazine,        5,6-dihydro-2H-[1,2]oxazine, 3,6-dihydro-2H-[1,2]oxazine,        3,4-dihydro-2H-[1,2]oxazine, 5,6-dihydro-4H-[1,2]thiazine,        5,6-dihydro-2H-[1,2] thiazine, 3,6-dihydro-2H-[1,2] thiazine,        3,4-dihydro-2H-[1,2] thiazine, 5,6-dihydro-2H-[1,3]oxazine,        5,6-dihydro-4H-[1,3]oxazine, 3,6-dihydro-2H-[1,3]oxazine,        3,4-dihydro-2H-[1,3]oxazine, 3,6-dihydro-2H-[1,4]oxazine,        3,4-dihydro-2H-[1,4]oxazine, 5,6-dihydro-2H-[1,3]thiazine,        5,6-dihydro-4H-[1,3]thiazine, 3,6-dihydro-2H-[1,3]thiazine,        3,4-dihydro-2H-[1,3]thiazine, 3,6-dihydro-2H-[1,4]thiazine,        3,4-dihydro-2H-[1,4]thiazine,        1,2,3,6-tetrahydro-[1,2,4]triazine,        1,2,3,4-tetrahydro-[1,2,4]triazine,        1,2,3,4-tetrahydro-[1,3,5]triazine,        2,3,4,5-tetrahydro-[1,2,4]triazine,        1,4,5,6-tetrahydro-[1,2,4]triazine,        5,6-dihydro-[1,4,2]dioxazine, 5,6-dihydro-[1,4,2]dioxazine,        5,6-dihydro-[1,4,2]dithiazine, 2,3-dihydro-[1,4,2]dioxazine,        3,4-dihydro-2H-[1,3,4]oxadiazine,        3,6-dihydro-2H-[1,3,4]oxadiazine,        3,4-dihydro-2H-[1,3,5]oxadiazine,        3,6-dihydro-2H-[1,3,5]oxadiazine,        5,6-dihydro-2H-[1,2,5]oxadiazine,        5,6-dihydro-4H-[1,2,5]oxadiazine,        3,4-dihydro-2H-[1,3,4]thiadiazine,        3,6-dihydro-2H-[1,3,4]thiadiazine,        3,4-dihydro-2H-[1,3,5]thiadiazine,        3,6-dihydro-2H-[1,3,5]thiadiazine,        5,6-dihydro-2H-[1,2,5]thiadiazine,        5,6-dihydro-4H-[1,2,5]thiadiazine,        5,6-dihydro-2H-[1,2,3]oxadiazine,        3,6-dihydro-2H-[1,2,5]oxadiazine,        5,6-dihydro-4H-[1,3,4]oxadiazine,        3,4-dihydro-2H-[1,2,5]oxadiazine,        5,6-dihydro-2H-[1,2,3]thiadiazine,        3,6-dihydro-2H-[1,2,5]thiadiazine,        5,6-dihydro-4H-[1,3,4]thiadiazine,        3,4-dihydro-2H-[1,2,5]thiadiazine,        5,6-dihydro-[1,4,3]oxathiazine, 5,6-dihydro-[1,4,2]oxathiazine,        2,3-dihydro-[1,4,3]oxathiazine, 2,3-dihydro-[1,4,2]oxathiazine,        4,5-dihydropyridine, 1,6-dihydropyridine, 5,6-dihydropyridine,        2H-pyran, 2H-thiin, 3,6-dihydropyridine, 2,3-dihydropyridazine,        2,5-dihydropyridazine, 4,5-dihydropyridazine,        1,2-dihydropyridazine, 2,3-dihydropyrimidine,        2,5-dihydropyrimidine, 5,6-dihydropyrimidine,        3,6-dihydropyrimidine, 4,5-dihydropyrazine, 5,6-dihydropyrazine,        3,6-dihydropyrazine, 4,5-dihydropyrazine, 1,4-dihydropyrazine,        1,4-dithiin, 1,4-dioxin, 2H-1,2-oxazine, 6H-1,2-oxazine,        4H-1,2-oxazine, 2H-1,3-oxazine, 4H-1,3-oxazine, 6H-1,3-oxazine,        2H-1,4-oxazine, 4H-1,4-oxazine, 2H-1,3-thiazine,        2H-1,4-thiazine, 4H-1,2-thiazine, 6H-1,3-thiazine,        4H-1,4-thiazine, 2H-1,2-thiazine, 6H-1,2-thiazine, 1,4-oxathiin,        2H,5H-1,2,3-triazine, 1H,4H-1,2,3-triazine,        4,5-dihydro-1,2,3-triazine, 1H,6H-1,2,3-triazine,        1,2-dihydro-1,2,3-triazine, 2,3-dihydro-1,2,4-triazine,        3H,6H-1,2,4-triazine, 1H,6H-1,2,4-triazine,        3,4-dihydro-1,2,4-triazine, 1H,4H-1,2,4-triazine,        5,6-dihydro-1,2,4-triazine, 4,5-dihydro-1,2,4-triazine,        2H,5H-1,2,4-triazine, 1,2-dihydro-1,2,4-triazine,        1H,4H-1,3,5-triazine, 1,2-dihydro-1,3,5-triazine,        1,4,2-dithiazine, 1,4,2-dioxazine, 2H-1,3,4-oxadiazine,        2H-1,3,5-oxadiazine, 6H-1,2,5-oxadiazine, 4H-1,3,4-oxadiazine,        4H-1,3,5-oxadiazine, 4H-1,2,5-oxadiazine, 2H-1,3,5-thiadiazine,        6H-1,2,5-thiadiazine, 4H-1,3,4-thiadiazine,        4H-1,3,5-thiadiazine, 4H-1,2,5-thiadiazine,        2H-1,3,4-thiadiazine, 6H-1,3,4-thiadiazine, 6H-1,3,4-oxadiazine        and 1,4,2-oxathiazine, wherein the heterocycle is optionally        vicinally fused with a saturated or unsaturated 5-, 6- or        7-membered ring containing 0, 1 or 2 atoms independently        selected from N, O and S;    -   R^(c) is independently, in each instance, phenyl substituted by        0, 1 or 2 groups selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl,        —OR^(a) and —NR^(a)R^(a); or R^(c) is a saturated or unsaturated        5- or 6-membered ring heterocycle containing 1, 2 or 3        heteroatoms independently selected from N, O and S, wherein no        more than 2 of the ring members are O or S, wherein the        heterocycle is optionally fused with a phenyl ring, and the        carbon atoms of the heterocycle are substituted by 0, 1 or 2 oxo        groups, wherein the heterocycle or fused phenyl ring is        substituted by 0, 1, 2 or 3 substituents selected from halo,        C₁₋₄alkyl, C₁₋₃haloalkyl, —OR^(a) and —NR^(a)R^(a);    -   R^(d) is hydrogen or —CH₃;    -   R^(e) is, independently, in each instance, C₁₋₉-alkyl        substituted by 0, 1, 2, 3 or 4 substituents selected from halo,        cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),        —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),        —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),        —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(e),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(O)R^(b), N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); and        wherein the C₁₋₉alkyl is additionally substituted by 0 or 1        groups independently selected from R^(g);    -   R^(f) is, independently, in each instance, R^(e) or H; and    -   R^(g) is, independently, in each instance, a saturated or        unsaturated 5- or 6-membered monocyclic ring containing 1, 2 or        3 atoms selected from N, O and S, so long as the combination of        O and S atoms is not greater than 2, wherein the carbon atoms of        the ring are substituted by 0 or 1 oxo groups.

In one embodiment, in conjunction with any one of the above and belowembodiments, X is ═N— or ═C(R²)—; Y is —N— or ═C(R³)—, wherein at leastone of X and Y is not ═N—.

In another embodiment, in conjunction with any one of the above andbelow embodiments, X is ═C(R²)—; Y is ═C(R³)—; and R³ is halo, —NH₂,—NHC₁₋₃alkyl, —N(C₁₋₃alkyl)C₁₋₃alkyl, or C₁₋₃alkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, X is ═C(R^(e))—; Y is ═C(R³)—; and R³ is H;

In another embodiment, in conjunction with any one of the above andbelow embodiments, X is ═N—; and Y is ═C(R³)—.

In another embodiment, in conjunction with any one of the above andbelow embodiments, X is ═C(R²)—; and Y is ═N—.

Sub-embodiment A: In another embodiment, in conjunction with any one ofthe above and below embodiments, R¹ is

or R¹ is a naphthyl substituted by 0, 1, 2 or 3 substituentsindependently selected from R⁵; or R¹ is R^(b) substituted by 1, 2 or 3substituents independently selected from R⁵.

Sub-embodiment B: In another embodiment, in conjunction with any one ofthe above and below embodiments, R¹ is

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is a naphthyl substituted by 0, 1, 2 or 3substituents independently selected from R⁵.

Sub-embodiment C: In another embodiment, in conjunction with any one ofthe above and below embodiments, R¹ is R^(b) substituted by 1, 2 or 3substituents independently selected from R⁵.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R² is, independently, in each instance, R¹⁰,C₁₋₈alkyl substituted by 0, 1 or 2 substituents selected from R¹⁰,—(CH₂)_(n)phenyl substituted by 0, 1, 2 or 3 substituents independentlyselected from R¹⁰, or a saturated or unsaturated 5- or 6-membered ringheterocycle containing 1, 2 or 3 heteroatoms independently selected fromN, O and S, wherein no more than 2 of the ring members are O or S,wherein the heterocycle is optionally fused with a phenyl ring, and theheterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3substituents independently selected from R¹⁰.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R² is, independently, in each instance, R¹⁰,C₁₋₈alkyl substituted by 0, 1 or 2 substituents selected from R¹⁰,—(CH₂)phenyl substituted by 0, 1, 2 or 3 substituents independentlyselected from R¹⁰, or a saturated or unsaturated 5- or 6-membered ringheterocycle containing 1, 2 or 3 heteroatoms independently selected fromN, O and S, wherein no more than 2 of the ring members are O or S,wherein the heterocycle is optionally fused with a phenyl ring, and theheterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3substituents independently selected from R¹¹.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R² is C₁₋₈alkyl substituted by 0, 1 or 2 substituentsselected from R¹⁰.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R² is —(CH₂)₁₋₂phenyl substituted by 0, 1, 2 or 3substituents independently selected from R¹⁰.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R² is a saturated or unsaturated 5- or 6-memberedring heterocycle containing 1, 2 or 3 heteroatoms independently selectedfrom N, O and S, wherein no more than 2 of the ring members are O or S,wherein the heterocycle is optionally fused with a phenyl ring, and theheterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3substituents independently selected from R¹⁰.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R² is H.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R³ is, independently, in each instance, H, halo,—NH₂, —NHC₁₋₃alkyl, —N(C₁₋₃alkyl)C₁₋₃alkyl, or C₁₋₃alkyl; wherein, whenX is ═C(R²)— and Y is ═C(R³)— then at least one of R² and R³ is otherthan H.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R³ is halo, —NH₂, —NHC₁₋₃alkyl,—N(C₁₋₃alkyl)C₁₋₃alkyl, or C₁₋₃alkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R³ is H.

Sub-embodiment D: In another embodiment, in conjunction with any one ofthe above and below embodiments, R⁴ is

orR⁴ is a saturated or unsaturated 5- or 6-membered ring heterocyclecontaining 1, 2 or 3 atoms selected from O, N and S that is optionallyvicinally fused with a saturated or unsaturated 3- or 4-atom bridgecontaining 0, 1, 2 or 3 atoms selected from O, N and S with theremaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2, wherein the carbon atoms of the heterocycleand bridge are substituted by 0, 1, 2 or 3 substituents independentlyselected from R^(e), C₁₋₄haloalkyl, halo, nitro, cyano, oxo, —OR^(f),—S(═O)_(n)R^(e), —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —OC₁₋₆alkylC(═O)OR^(e), —NR^(a)R^(f),—NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(e), —C(═O)OR^(e), —OC(═O)R^(e),—C(═O)NR^(a)R^(f) and —NR^(a)C(═O)R^(e); and unsaturated carbon atomsmay be additionally substituted by ═O; and any available nitrogen atomsin the heterocycle and bridge are substituted by H, —C₁₋₆alkylOR^(f),R^(e), —C₁₋₆alkylNR^(a)R^(f), —C₁₋₃alkylC(═O)OR^(e),—C₁₋₃alkylC(═O)NR^(a)R^(f), —C₁₋₃alkylOC(═O)R^(e),—C₁₋₃alkylNR^(a)C(═O)R^(e), —C(═O)R^(c) or —C₁₋₃alkylR^(c); or R⁴ isnaphthyl substituted by 1, 2 or 3 substituents independently selectedfrom C₁₋₄haloalkyl, halo, nitro, cyano, —S(═O)_(n)R^(e),—OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—OC₁₋₆alkylC(═O)OR^(e), —NR^(a)C₁₋₄haloalkyl,—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(e),—C(═O)OR^(e), —OC(═O)R^(e) and —C(═O)NR^(a)R^(f); but in no instance isR⁴ 3,5-ditrifluoromethylphenyl or 3-trifluoromethyl-4-fluorophenyl,-phenyl-(C₁₋₈alkyl), -phenyl-O—(C₁₋₆alkyl), -phenyl-NR^(a)R^(a) or-phenyl-N(R^(a))C(═O)(C₁₋₈alkyl).

Sub-embodiment E: In another embodiment, in conjunction with any one ofthe above and below embodiments, R⁴ is

but in no instance is R⁴ 3,5-ditrifluoromethylphenyl or3-trifluoromethyl-4-fluorophenyl, -phenyl-(C₁₋₈alkyl),-phenyl-O—(C₁₋₆alkyl), -phenyl-NR^(a)R^(a) or-phenyl-N(R^(a))C(═O)(C₁₋₈alkyl).

Sub-embodiment F: In another embodiment, in conjunction with any one ofthe above and below embodiments, R⁴ is a saturated or unsaturated 5- or6-membered ring heterocycle containing 1, 2 or 3 atoms selected from O,N and S that is optionally vicinally fused with a saturated orunsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selectedfrom O, N and S with the remaining atoms being carbon, so long as thecombination of O and S atoms is not greater than 2, wherein the carbonatoms of the heterocycle and bridge are substituted by 0, 1, 2 or 3substituents independently selected from R^(e), C₁₋₄haloalkyl, halo,nitro, cyano, oxo, —OR^(f), —S(═O)_(n)R^(e), —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(a)R^(f), —OC₁₋₆alkylC(═O)OR^(c),—NR^(a)R^(f), —NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(e), —C(═O)OR^(e), —OC(═O)R^(e),—C(═O)NR^(a)R^(f) and —NR^(a)C(═O)R^(e); and unsaturated carbon atomsmay be additionally substituted by ═O; and any available nitrogen atomsin the heterocycle and bridge are substituted by H, —C₁₋₆alkylOR^(f),R^(e), —C₁₋₆alkylNR^(a)R^(f), —C₁₋₃alkylC(═O)OR^(e),—C₁₋₃alkylC(═O)NR^(a)R^(f), —C₁₋₃alkylOC(═O)R^(e),—C₁₋₃alkylNR^(a)C(═O)R^(e), —C(═O)R^(c) or —C₁₋₃alkylR^(c).

Sub-embodiment G: In another embodiment, in conjunction with any one ofthe above and below embodiments, R⁴ is a saturated or unsaturated 5- or6-membered ring heterocycle containing 1, 2 or 3 atoms selected from O,N and S that is vicinally fused with a saturated or unsaturated 3- or4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and Swith the remaining atoms being carbon, so long as the combination of Oand S atoms is not greater than 2, wherein the carbon atoms of theheterocycle and bridge are substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(e), C₁₋₄haloalkyl, halo, nitro, cyano,oxo, —OR^(f), —S(═O)_(n)R^(e), —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —OC₁₋₆alkylC(═O)OR^(e), —NR^(a)R^(f),—NR^(a)C₁₋₄haloalkyl, —NR^(a)R^(f)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(e), —C(═O)OR^(e), —OC(═O)R^(e),—C(═O)NR^(a)R^(f) and —NR^(a)C(═O)R^(e); and unsaturated carbon atomsmay be additionally substituted by ═O; and any available nitrogen atomsin the heterocycle and bridge are substituted by H, —C₁₋₆alkylOR^(f),R^(e), —C₁₋₆alkylNR^(a)R^(f), —C₁₋₃alkylC(═O)OR^(e),—C₁₋₃alkylC(═O)NR^(a)R^(f), —C₁₋₃alkylOC(═O)R^(e),—C₁₋₃alkylNR^(a)C(═O)R^(e), —C(═O)R^(c) or —C₁₋₃alkylR^(c).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is naphthyl substituted by 1, 2 or 3 substituentsindependently selected from C₁₋₄haloalkyl, halo, nitro, cyano,—S(O)_(n)R^(e), —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —OC₁₋₆alkylC(═O)OR^(e), —NR^(a)C₁₋₄haloalkyl,—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(e),—C(═O)OR^(e), —OC(═O)R^(e) and —C(═O)NR^(a)R^(f).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁵ is independently, at each instance, R^(f), R^(g),halo, nitro, cyano, —OR^(e), —OR^(g), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e),—OC(═O)NR^(a)R^(f), a phenyl ring substituted with 0, 1, 2, or 3substituents independently selected from R¹⁰; or R⁵ is a saturated orunsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atomsselected from O, N and S, substituted with 0, 1, 2, or 3 substituentsindependently selected from R¹⁰.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁵ is H.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁵ is R^(f) or R^(g).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁵ is independently, at each instance, R^(e), R^(g),halo, nitro, cyano, —OR^(e), —OR^(g), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e),—OC(═O)NR^(a)R^(f), a phenyl ring substituted with 0, 1, 2, or 3substituents independently selected from R¹⁰; or R⁵ is a saturated orunsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atomsselected from O, N and S, substituted with 0, 1, 2, or 3 substituentsindependently selected from R¹⁰.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁶ is independently, at each instance, H, C₁₋₅alkyl,C₁₋₄haloalkyl, halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a) or—NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a),—S(C₁₋₆alkyl), a phenyl ring substituted with 1, 2, or 3 substituentsindependently selected from R¹⁰; or R⁶ is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected fromO, N and S substituted with 0, 1, 2, or 3 substituents independentlyselected from R¹⁰.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁶ is independently, at each instance, C₁₋₅alkyl,C₁₋₄haloalkyl, halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a) or—NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a),—S(C₁₋₆-alkyl), a phenyl ring substituted with 1, 2, or 3 substituentsindependently selected from R¹⁰; or R⁶ is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected fromO, N and S substituted with 0, 1, 2, or 3 substituents independentlyselected from R¹⁰.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁶ is independently, at each instance, C₁₋₅alkyl,C₁₋₄haloalkyl, halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), NR^(a)R^(a),—NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a) or—NR^(a)C₂₋₆alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a) or —S(C₁₋₆alkyl).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁶ is a phenyl ring substituted with 1, 2, or 3substituents independently selected from R¹⁰.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁶ is a saturated or unsaturated 5- or 6-memberedring heterocycle containing 1, 2 or 3 atoms selected from O, N and Ssubstituted with 0, 1, 2, or 3 substituents independently selected fromR¹⁰.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁶ is H.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁷ is independently, at each instance, H,acyclicC₁₋₈alkyl, C₁₋₄haloalkyl, halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a), —NR^(a)C_(—)₄haloalkyl, —NR^(a)C₂ alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a),—C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a) or —S(C₁₋₆alkyl); or R⁷ is asaturated or unsaturated 4- or 5-membered ring heterocycle containing asingle nitrogen atom, wherein the ring is substituted with 0, 1 or 2substituents independently selected from halo, C₁₋₂haloalkyl andC₁₋₃alkyl.

Sub-embodiment H: In another embodiment, in conjunction with any one ofthe above and below embodiments, R⁷ is independently, at each instance,acyclicC₁₋₈alkyl, C₁₋₄haloalkyl, halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)C₁₋₄haloalkyl, —NR^(a) C₂₋₆alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a) or—S(C₁₋₆alkyl); or R⁷ is a saturated or unsaturated 4- or 5-membered ringheterocycle containing a single nitrogen atom, wherein the ring issubstituted with 0, 1 or 2 substituents independently selected fromhalo, C₁₋₂haloalkyl and C₁₋₃alkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁷ is H.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁷ is a saturated or unsaturated 4- or 5-memberedring heterocycle containing a single nitrogen atom, wherein the ring issubstituted with 0, 1 or 2 substituents independently selected fromhalo, C₁₋₂haloalkyl and C₁₋₃alkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁷ is independently, at each instance,acyclicC₁₋₈alkyl, C₁₋₄haloalkyl, halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a) or—S(C₁₋₆alkyl).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁷ is independently, at each instance,acyclicC₁₋₈alkyl, C₁₋₄haloalkyl, Br, or Cl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁷ is independently, at each instance,acyclicC₁₋₈alkyl or C₁₋₄haloalkyl.

Sub-embodiment I: In another embodiment, in conjunction with any one ofthe above and below embodiments, R⁷ is independently, at each instance,C₃₋₅alkyl or C₁₋₂haloalkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁷ is C₃₋₅alkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁷ is —C(CH₃)₃.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁷ is —CF₃.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁸ is independently, at each instance, H, C₁₋₅alkyl,C₁₋₄haloalkyl, halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a),—S(C₁₋₆alkyl), a phenyl ring substituted with 1, 2, or 3 substituentsindependently selected from R¹⁰, or R⁸ is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected fromO, N and S substituted with 0, 1, 2, or 3 substituents independentlyselected from R¹⁰.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁸ is H.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁸ is independently, at each instance, C₁₋₅alkyl,C₁₋₄haloalkyl, halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a),—S(C₁₋₆alkyl), a phenyl ring substituted with 1, 2, or 3 substituentsindependently selected from R¹⁰, or R⁸ is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected fromO, N and S substituted with 0, 1, 2, or 3 substituents independentlyselected from R¹⁰.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁸ is independently, at each instance, C₁₋₅alkyl,C₁₋₄haloalkyl, halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a) or—S(C₁₋₆alkyl).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁸ is a phenyl ring substituted with 1, 2, or 3substituents independently selected from R¹⁰.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁸ is a saturated or unsaturated 5- or 6-memberedring heterocycle containing 1, 2 or 3 atoms selected from O, N and Ssubstituted with 0, 1, 2, or 3 substituents independently selected fromR¹⁰.

Sub-embodiment J: In another embodiment, in conjunction with any one ofthe above and below embodiments, R⁹ is independently, at each instance,R^(f), R^(g), halo, nitro, cyano, —OR^(e), —OR^(g),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(g), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e),—OC(═O)NR^(a)R^(f), a phenyl ring substituted with 0, 1, 2, or 3substituents independently selected from R¹⁰; or R⁹ is a saturated orunsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atomsselected from O, N and S substituted with 0, 1, 2, or 3 substituentsindependently selected from R¹⁰; wherein at least one of R⁵, R⁶, R⁷, R⁸and R⁹ is C₁₋₈alkyl, C₁₋₄haloalkyl, halo, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)C₁₋₄haloalkyl,—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a),—C₁₋₆alkylNR^(a)R^(a) or —S(C₁₋₆alkyl); or R⁹ is a saturated orunsaturated 4- or 5-membered ring heterocycle containing a singlenitrogen atom, wherein the ring is substituted with 0, 1 or 2substituents independently selected from halo, C₁₋₂haloalkyl andC₁₋₃alkyl.

Sub-embodiment K: In another embodiment, in conjunction with any one ofthe above and below embodiments, R⁹ is H.

Sub-embodiment L: In another embodiment, in conjunction with any one ofthe above and below embodiments, R⁹ is independently, at each instance,R^(e), R^(g), halo, nitro, cyano, —OR^(e), —OR^(g),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆ alkylOR^(f), —NR^(a)R^(f),—NR^(a)R¹⁻⁸alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e) —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e),—OC(═O)NR^(a)R^(f), a phenyl ring substituted with 0, 1, 2, or 3substituents independently selected from R¹⁰; or R⁹ is a saturated orunsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atomsselected from O, N and S substituted with 0, 1, 2, or 3 substituentsindependently selected from R¹⁰; wherein at least one of R⁵, R⁶, R⁷, R⁸and R⁹ is C₁₋₈alkyl, C₁₋₄haloalkyl, halo, —OC₁₋₄haloalkyl, —OC₂₋₆NR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)C₁₋₄haloalkyl,—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a),—C₁₋₆alkylNR^(a)R^(a) or —S(C₁₋₆alkyl); or R⁹ is a saturated orunsaturated 4- or 5-membered ring heterocycle containing a singlenitrogen atom, wherein the ring is substituted with 0, 1 or 2substituents independently selected from halo, C₁₋₂haloalkyl andC₁₋₃alkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁹ is independently, at each instance, R^(e).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁹ is independently, at each instance, R^(g).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁹ is independently, at each instance, halo, nitro,cyano, —OR^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f),—NR^(a)R^(g), —NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f),—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) or—OC(═O)NR^(a)R^(f).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁹ is independently, at each instance, a phenyl ringsubstituted with 0, 1, 2, or 3 substituents independently selected fromR¹⁰; or R⁹ is a saturated or unsaturated 5- or 6-membered ringheterocycle containing 1, 2 or 3 atoms selected from O, N and Ssubstituted with 0, 1, 2, or 3 substituents independently selected fromR¹⁰.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁹ is a saturated or unsaturated 4- or 5-memberedring heterocycle containing a single nitrogen atom, wherein the ring issubstituted with 0, 1 or 2 substituents independently selected fromhalo, C₁₋₂haloalkyl and C₁₋₃alkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹⁰ is independently, at each instance, selected fromH, C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR,—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁰ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl) —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁰ isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—C₂₋₆alkylOR^(a), SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

Sub-embodiment M: In another embodiment, in conjunction with any one ofthe above and below embodiments, R¹⁰ is H.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹⁰ is independently, at each instance, selected fromC₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₁₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁰ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a) and—NR^(a)C₂₋₆alkylOR^(a); or R¹⁰ is C₁₋₄alkyl substituted by 0, 1, 2 or 3groups selected from C₁₋₄haloalkyl, halo, cyano, nitro,—C(═O)(C₁₋₈alkyl), —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹¹ is independently, at each instance, selected fromH, C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkyNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a) C₂₋₆alkylOR^(a); or R¹¹ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a), —OC₂alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkyNR^(a)R^(a) and —NR^(a) C₂₋₆alkylOR^(a); or R¹¹ isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁰ and R¹¹together are a saturated or unsaturated 3- or 4-atom bridge containing1, 2 or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the bridge is substituted by 0, 1 or 2 substituents selectedfrom ═O, R^(e), halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(e),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(f))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(f), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(f))C(═O)R^(e),—S(═O)₂N(R^(f))C(═O)OR^(e), —S(═O)₂N(R^(f))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(f))C(═O)R^(e), —N(R^(f))C(═O)OR^(e),—N(R^(f))C(═O)NR^(a)R^(f), —N(R^(f))C(═NR^(a))NR^(a)R^(f),—N(R^(f))S(═O)₂R^(e), —N(R^(f))S(═O)₂NR^(a)R^(f),—NR^(f)C₂₋₆alkylNR^(a)R^(f) and —NR^(f)C₂₋₆alkylOR^(f).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹¹ is independently, at each instance, selected fromC₁₋₈alkyl, cyano, nitro, —C(═O)(C₁₋₈alkyl), —C(═O)O(C₁₋₈alkyl),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)(C₁₋₈alkyl),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl),—S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹¹ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹¹ isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁰ and R¹¹together are a saturated or unsaturated 3- or 4-atom bridge containing1, 2 or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the bridge is substituted by 0, 1 or 2 substituents selectedfrom ═O, R^(e), halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(e),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(f))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylR^(f), —SR^(f), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(f))C(═O)R^(e),—S(═O)₂N(R^(f))C(═O)OR^(e), —S(═O)₂N(R^(f))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(f))C(═O)R^(e), —N(R^(f))C(═O)OR^(e),—N(R^(f))C(═O)NR^(a)R^(f), —N(R^(f))C(═NR^(a))NR^(a)R^(f),—N(R^(f))S(═O)₂R^(e), —N(R^(f))S(═O)₂NR^(a)R^(f),—NR^(f)C₂₋₆alkylNR^(a)R^(f) and —NR^(f)C₂₋₆alkylOR^(f).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹¹ is independently, at each instance, selected fromC₁₋₈alkyl, cyano, nitro, —C(═O)(C₁₋₈alkyl), —C(═O)O(C₁₋₈alkyl),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)(C₁₋₈alkyl),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl),—S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹¹ is a saturated or unsaturated 5-, 6- or7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclicring containing 1, 2 or 3 atoms selected from N, O and S, wherein thering is fused with 0 or 1 benzo groups and 0 or 1 saturated orunsaturated 5-, 6- or 7-membered heterocyclic ring containing 1, 2 or 3atoms selected from N, O and S; wherein the carbon atoms of the ring aresubstituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by0, 1, 2 or 3 groups selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)(C₁₋₈alkyl), —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹¹ is C₁₋₄alkyl substituted by 0, 1, 2 or 3 groupsselected from C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

Sub-embodiment N: In another embodiment, in conjunction with any one ofthe above and below embodiments, R¹⁰ and R¹¹ together are a saturated orunsaturated 3- or 4-atom bridge containing 1, 2 or 3 atoms selected fromO, N and S with the remaining atoms being carbon, so long as thecombination of O and S atoms is not greater than 2, wherein the bridgeis substituted by 0, 1 or 2 substituents selected from ═O, R^(e), halo,cyano, nitro, —C(═O)R^(e), —C(═O)OR^(e), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(f))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(f), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(f))C(═O)R^(e), —S(═O)₂N(R^(f))C(═O)OR^(e),—S(═O)₂N(R^(f))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(f))C(═O)R^(e),—N(R^(f))C(═O)OR^(e), —N(R^(f))C(═O)NR^(a)R^(f),—N(R^(f))C(═NR^(a))NR^(a)R^(f), —N(R^(f))S(═O)₂R^(e),—N(R^(f))S(═O)₂NR^(a)R^(f), —NR^(f)C₂₋₆alkylNR^(a)R^(f) and—NR^(f)C₂₋₆alkylOR^(f).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹⁰ and R¹¹ together are a saturated or unsaturated3-atom bridge containing 1, 2 or 3 atoms selected from O, N and S withthe remaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2, wherein the bridge is substituted by 0, 1or 2 substituents selected from ═O, R^(e), halo, cyano, nitro,—C(═O)R^(e), —C(═O)OR^(e), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f),—OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(f))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(f), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(f))C(═O)R^(e),—S(═O)₂N(R^(f))C(═O)OR^(e), —S(═O)₂N(R^(f))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(f))C(═O)R^(e), —N(R^(f))C(═O)OR^(e),—N(R^(f))C(═O)NR^(a)R^(f), —N(R^(f))C(═NR^(a))NR^(a)R^(f),—N(R^(f))S(═O)₂R^(e), —N(R^(f))S(═O)₂NR^(a)R^(f),—NR^(f)C₂₋₆alkylNR^(a)R^(f) and —NR^(f)C₂₋₆alkylOR^(f).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹⁰ and R¹¹ together are a saturated or unsaturated4-atom bridge containing 1, 2 or 3 atoms selected from O, N and S withthe remaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2, wherein the bridge is substituted by 0, 1or 2 substituents selected from ═O, R^(e), halo, cyano, nitro,—C(═O)R^(e), —C(═O)OR^(e), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f),—OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(e))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(f), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(f))C(═O)R^(e),—S(═O)₂N(R^(f))C(═O)OR^(e), —S(═O)₂N(R^(f))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(f))C(═O)R^(e), —N(R^(f))C(═O)OR^(e),N(R^(f))C(═O)NR^(a)R^(f), —N(R^(f))C(═NR^(a))NR^(a)R^(f),—N(R^(f))S(═O)₂R^(e), —N(R^(f))S(═O)₂NR^(a)R^(f),—NR^(f)C₂₋₆alkylNR^(a)R^(f) and —NR^(f)C₂₋₆alkylOR^(f).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹⁰ and R¹¹ together are a saturated or unsaturated3- or 4-atom bridge containing 1, 2 or 3 atoms selected from O, N and Swith the remaining atoms being carbon, so long as the combination of Oand S atoms is not greater than 2, wherein the bridge is substituted by1 or 2 substituents selected from R^(e), halo, cyano, nitro,—C(═O)R^(e), —C(═O)OR^(e), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f),—OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(f))S(═O)₂R^(a)R^(f), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(f), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(f))C(═O)R^(e),—S(═O)₂N(R^(f))C(═O)OR^(e), —S(═O)₂N(R^(f))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(f))C(═O)R^(e), —N(R^(f))C(═O)OR^(f),—N(R^(f))C(═O)NR^(a)R^(f), —N(R^(f))C(═NR^(a))NR^(a)R^(f),—N(R^(f))S(═O)₂R^(e), —N(R^(f))S(═O)₂NR^(a)R^(f),—NR^(f)C₂₋₆alkylNR^(a)R^(f) and —NR^(f)C₂₋₆alkylOR^(f).

Sub-embodiment O: In another embodiment, in conjunction with any one ofthe above and below embodiments, R¹⁰ and R¹¹ together are a saturated orunsaturated 3-atom bridge containing 1 or 2 atoms selected from O, N andS with the remaining atoms being carbon, wherein the bridge issubstituted by 1 or 2 substituents selected from R^(e), halo, cyano,nitro, —C(═O)R^(e), —C(═O)OR^(e), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(f))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(f), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(f))C(═O)R^(e), —S(═O)₂N(R^(f))C(═O)OR^(e),—S(═O)₂N(R^(f))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(f))C(═O)R^(e),—N(R^(f))C(═O)OR^(e), —N(R^(f))C(═O)NR^(a)R^(f),—N(R^(f))C(═NR^(a))NR^(a)R^(f), —N(R^(f))S(═O)₂R^(e),—N(R^(f))S(═O)₂NR^(a)R^(f), —NR^(f)C₂₋₆alkylNR^(a)R^(f) and—NR^(f)C₂₋₆alkylOR^(f).

Sub-embodiment P: In another embodiment, in conjunction with any one ofthe above and below embodiments, R¹⁰ and R¹¹ together are a saturated orunsaturated 3-atom bridge containing 1 or 2 atoms selected from O, N andS with the remaining atoms being carbon, wherein the bridge issubstituted by a substituents selected from R^(e), —C(═O)R^(e),—C(═O)OR^(e), —C(═O)NR^(a)R^(f), —OR, —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(f))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(f), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(f))C(═O)R^(e), —S(═O)₂N(R^(f))C(═O)OR^(e),—S(═O)₂N(R^(f))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(f))C(═O)R^(e),—N(R^(f))C(═O)OR^(e), —N(R^(f))C(═O)NR^(a)R^(f),—N(R^(f))C(═NR^(a))NR^(a)R^(f), —N(R^(f))S(═O)₂R^(e),—N(R^(f))S(═O)₂NR^(a)R^(f), —NR^(f)C₂₋₆alkylNR^(a)R^(f) and—NR^(f)C₂₋₆alkylOR^(f); and the bridge is additionally substituted by 0or 1 substituents selected from R^(e), oxo, halo, cyano, nitro,—C(═O)R^(e), —C(═O)OR^(e), —C(═O)NR^(a)R^(f),—C(═NR^(a)R^(f))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(f))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(f), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(f))C(═O)R^(e), —S(═O)₂N(R^(f))C(═O)OR^(e),—S(═O)₂N(R^(f))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(f)C(═O)R^(e),—N(R^(f))C(═O)OR^(e), —N(R^(f))C(═O)NR^(a)R^(f),—N(R^(f))C(═NR^(a))NR^(a)R^(f), —N(R^(f))S(═O)₂R^(e),—N(R^(f))S(═O)₂NR^(a)R^(f), —NR^(f)C₂₋₆alkylNR^(a)R^(f) and—NR^(f)C₂₋₆alkylOR^(f).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹⁰ and R¹¹ together are a saturated or unsaturated3-atom bridge containing 1 or 2 atoms selected from O, N and S with theremaining atoms being carbon, wherein the bridge is substituted by asubstituents selected from —C(═O)R^(e), —C(═O)OR^(e), —C(═O)NR^(a)R^(f),—OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(f))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(f), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(f))C(═O)R^(e),—S(═O)₂N(R^(f))C(═O)OR^(e), —S(═O)₂N(R^(f))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(f))C(═O)R^(e), —N(R^(f))C(═O)OR^(e),—N(R^(f))C(═O)NR^(a)R^(f), —N(R^(f))C(═NR^(a))NR^(a)R^(f),—N(R^(f))S(═O)₂R^(e), —N(R^(f))S(═O)₂NR^(a)R^(f),—NR^(f)C₂₋₆alkylNR^(a)R^(f) and —NR^(f)C₂₋₆alkylOR^(f).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹² is independently, at each instance, selected fromH, C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹² is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹² isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), N(R^(a))C(═O)(C₁₋₈alkyl) —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); wherein if R¹¹or R¹³ is CF₃, then R¹² is not F; or R¹¹ and R¹² together are asaturated or unsaturated 3- or 4-atom bridge containing 1, 2 or 3 atomsselected from O, N and S with the remaining atoms being carbon, so longas the combination of O and S atoms is not greater than 2, wherein thebridge is substituted by 0, 1 or 2 substituents selected from ═O, R^(e),halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(e), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(f))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(f), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(f))C(═O)R^(e), —S(═O)₂N(R^(f))C(═O)OR^(e),—S(═O)₂N(R^(f))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(f))C(═O)R^(e),—N(R^(f))C(═O)OR^(e), —N(R^(f))C(═O)NR^(a)R^(f),—N(R^(f))C(═NR^(a))NR^(a)R^(f), —N(R^(f))S(═O)₂R^(e),—N(f)S(═O)₂NR^(a)R^(f), —NR^(f)C₂₋₆alkylNR^(a)R^(f) and—NR^(f)C₂₋₆alkylOR^(e); wherein when R³ is NH₂, then -R¹¹-R¹²- is not—C═C—C═N— or any substituted version thereof.

Sub-embodiment Q: In another embodiment, in conjunction with any one ofthe above and below embodiments, R¹² is H.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹² is independently, at each instance, selected fromC₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹² is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹² isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); wherein if R¹¹or R¹³ is CF₃, then R¹² is not F; or R¹¹ and R¹² together are asaturated or unsaturated 3- or 4-atom bridge containing 1, 2 or 3 atomsselected from O, N and S with the remaining atoms being carbon, so longas the combination of O and S atoms is not greater than 2, wherein thebridge is substituted by 0, 1 or 2 substituents selected from ═O, R^(e),halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(e), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(f))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(f), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(f))C(═O)R^(e), —S(═O)₂N(R^(f))C(═O)OR^(e),—S(═O)₂N(R^(f))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(f))C(═O)R^(e),—N(R^(f))C(═O)OR^(e), —N(R^(f))C(═O)NR^(a)R^(f),—N(R^(f))C(═NR^(a))NR^(a)R^(f), —N(R^(f))S(═O)₂R^(e),—N(R^(f))S(═O)₂NR^(a)R^(f), —NR^(f)C₂₋₆alkylNR^(a)R^(f) and —NR^(f)C₂alkylOR^(f); wherein when R³ is NH₂, then -R¹¹-R¹²- is not —C═C—C═N— orany substituted version thereof.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹² is a saturated or unsaturated 5-, 6- or7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclicring containing 1, 2 or 3 atoms selected from N, O and S, wherein thering is fused with 0 or 1 benzo groups and 0 or 1 saturated orunsaturated 5-, 6- or 7-membered heterocyclic ring containing 1, 2 or 3atoms selected from N, O and S; wherein the carbon atoms of the ring aresubstituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by0, 1, 2 or 3 groups selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)(C₁₋₈alkyl), —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

Sub-embodiment R: In another embodiment, in conjunction with any one ofthe above and below embodiments, R¹¹ and R¹² together are a saturated orunsaturated 3- or 4-atom bridge containing 1, 2 or 3 atoms selected fromO, N and S with the remaining atoms being carbon, so long as thecombination of O and S atoms is not greater than 2, wherein the bridgeis substituted by 0, 1 or 2 substituents selected from ═O, R^(e), halo,cyano, nitro, —C(═O)R^(e), —C(═O)OR^(e), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)NR^(a)R^(f))S(═O)₂R^(e), OC₂₋₆alkylNR^(a)R^(f), —SR^(f),—S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(f))C(═O)R^(e), —S(═O)₂N(R^(f))C(═O)OR^(e),—S(═O)₂N(R^(f))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(f))C(═O)R^(e),—N(R^(f))C(═O)OR^(e), —N(R^(f))C(═O)NR^(a)R^(f),—N(R^(f))C(═NR^(a))NR^(a)R^(f), —N(R^(f))S(═O)₂R^(e),—N(R^(f))S(═O)₂NR^(a)R^(f), —NR^(f)C₂₋₆alkylNR^(a)R^(f) and—NR^(f)C₂₋₆alkylOR^(f); wherein when R³ is NH₂, then -R¹¹-R¹²- is not—C═C—C═N— or any substituted version thereof.

Sub-embodiment S: In another embodiment, in conjunction with any one ofthe above and below embodiments, R¹¹ and R¹² together are a saturated orunsaturated 3-atom bridge containing 1, 2 or 3 atoms selected from O, Nand S with the remaining atoms being carbon, so long as the combinationof O and S atoms is not greater than 2, wherein the bridge issubstituted by 0, 1 or 2 substituents selected from ═O, R^(e), halo,cyano, nitro, —C(═O)R^(e), —C(═O)OR^(e), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(f))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(f), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(f))C(═O)R^(e), —S(═O)₂N(R^(f))C(═O)OR^(e),—S(═O)₂N(R^(f))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(f))C(═O)R^(e),—N(f)C(═O)OR^(e), —N(R^(f))C(═O)NR^(a)R^(f),—N(R^(f))C(═NR^(a))NR^(a)R^(f), —N(R^(f))S(═O)₂R^(e),—N(R^(f))S(═O)₂NR^(a)R^(f), —NR^(f)C₂₋₆alkylNR^(a)R^(f) and—NR^(f)C₂₋₆alkylOR^(f).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹¹ and R¹² together are a saturated or unsaturated3-atom bridge containing 1 or 2 atoms selected from O, N and S with theremaining atoms being carbon, wherein the bridge is substituted by 0, 1or 2 substituents selected from ═O, R^(e), halo, cyano, nitro,—C(═O)R^(e), —C(═O)OR^(e), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f),—OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(f))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(f), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(f))C(═O)R^(e),—S(═O)₂N(R^(f))C(═O)OR^(e), —S(═O)₂N(R^(f))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(f))C(═O)R^(e), —N(R^(f))C(═O)OR^(e),—N(R^(f))C(═O)NR^(a)R^(f), —N(R^(f))C(═NR^(a))NR^(a)R^(f),—N(R^(f))S(═O)₂R^(e), —N(R^(f))S(═O)₂NR^(a)R^(f),—NR^(f)C₂₋₆alkylNR^(a)R^(f) and —NR^(f)C₂₋₆alkylOR^(f).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹¹ and R¹² together are a saturated or unsaturated3-atom bridge containing 1 or 2 atoms selected from O, N and S with theremaining atoms being carbon, wherein the bridge is substituted by 1 or2 substituents selected from ═O, R^(e), halo, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(e), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(f))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(f), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(f))C(═O)R^(e),—S(═O)₂N(R^(f))C(═O)OR^(e), —S(═O)₂N(R^(f))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(f))C(═O)R^(e), —N(R^(f))C(═O)OR^(e),—N(R^(f))C(═O)NR^(a)R^(f), —N(R^(f))C(═NR^(a))NR^(a)R^(f),—N(R^(f))S(═O)₂R^(e), —N(R^(f))S(═O)₂NR^(a)R^(f),—NR^(f)C₂₋₆alkylNR^(a)R^(f) and —NR^(f)C₂₋₆alkylOR^(f).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹¹ and R¹² together are a saturated or unsaturated3-atom bridge containing 1 or 2 atoms selected from O, N and S with theremaining atoms being carbon, wherein the bridge is substituted byR^(e), —C(═O)R^(e), —C(═O)OR^(e), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(f))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(f), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(f))C(═O)R^(e), —S(═O)₂N(R^(f))C(═O)OR^(e),—S(═O)₂N(R^(f))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(f))C(═O)R^(e),—N(R^(f))C(═O)OR^(e), —N(R^(f))C(═O)NR^(a)R^(f),—N(R^(f))C(═NR^(a))NR^(a)R^(f), —N(R^(f))S(═O)₂R^(e),—N(R^(f))S(═O)₂NR^(a)R^(f), —NR^(f)C₂₋₆alkylNR^(a)R^(f) or—NR^(f)C₂₋₆alkylOR^(f).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹¹ and R¹² together are a saturated or unsaturated3-atom bridge containing 1 or 2 atoms selected from O, N and S with theremaining atoms being carbon, wherein the bridge is substituted by—C(═O)R^(e), —C(═O)OR^(e), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(f))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(f), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(f))C(═O)R^(e),—S(═O)₂N(R^(f))C(═O)OR^(e), —S(═O)₂N(R^(f))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(f))C(═O)R^(e), —N(R^(e))C(═O)OR^(e),—N(R^(f))C(═O)NR^(a)R^(f), —N(R^(f))C(═NR^(a))NR^(a)R^(f),—N(R^(f))S(═O)₂R^(e), —N(R^(f))S(═O)₂NR^(a)R^(f),—NR^(f)C₂₋₆alkylNR^(a)R^(f) or —NR^(f)C₂₋₆alkylOR^(f).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹¹ and R¹² together are a saturated or unsaturated4-atom bridge containing 1, 2 or 3 atoms selected from O, N and S withthe remaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2 and first attachment atom in R¹² is not N,wherein the bridge is substituted by 0, 1 or 2 substituents selectedfrom ═O, R^(e), halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(e),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(e), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(f))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(f), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(f))C(═O)R^(e),—S(═O)₂N(R^(f))C(═O)OR^(e), —S(═O)₂N(R^(f))C(═O)NR^(a)R^(f), —NR^(a)R,—N(R^(f))C(═O)R^(e), —N(R^(f))C(═O)OR^(e), —N(R^(f))C(═O)NR^(a)R^(f),—N(R^(f))C(═NR^(a))NR^(a)R^(f), —N(R^(f))S(═O)₂R^(e),—N(R^(f))S(═O)₂NR^(a)R^(f), —NR^(f)C₂₋₆alkylNR^(a)R^(f) and—NR^(f)C₂₋₆alkylOR^(f).

Sub-embodiment T: In another embodiment, in conjunction with any one ofthe above and below embodiments, R¹¹ and R¹² together form a -R¹¹-R¹²-bridge selected from —O—C≡C—O—, —N—C≡C—C— and —N═C—C═C—, wherein thebridge is substituted by 0, 1 or 2 substituents selected from ═O, R^(e),halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(e), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(f))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(f), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(f))C(═O)R^(e), —S(═O)₂N(R^(f))C(═O)OR^(e),—S(═O)₂N(R^(f))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(f))C(═O)R^(e),—N(R^(f))C(═O)OR^(e), —N(R^(f))C(═O)NR^(a)R^(f),—N(R^(f))C(═NR^(a))NR^(a)R^(f), —N(R^(f))S(═O)₂R^(e),—N(R^(f))S(═O)₂NR^(a)R^(f), —NR^(f)C₂₋₆alkylNR^(a)R^(f) and—NR^(f)C₂₋₆alkylOR^(f).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹¹ and R¹² together form a -R¹¹-R¹²- bridge selectedfrom —O—C≡C—O—, —N—C≡C—C— and —N═C—C═C—, wherein the bridge issubstituted by 1 or 2 substituents selected from ═O, R^(e), halo, cyano,nitro, —C(═O)R^(e), —C(═O)OR^(e), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(f))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(f), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(f))C(═O)R^(e), —S(═O)₂N(R^(f))C(═O)OR^(e),—S(═O)₂N(R^(f))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(f))C(═O)R^(e),—N(R^(f))C(═O)OR^(e), —N(R^(f))C(═O)NR^(a)R^(f),—N(R^(f))C(═NR^(a))NR^(a)R^(f), —N(R^(f))S(═O)₂R^(e),—N(R^(f))S(═O)₂NR^(a)R^(f), —NR^(f)C₂₋₆alkylNR^(a)R^(f) and—NR^(f)C₂₋₆alkylOR^(f).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹³ is independently, at each instance, selected fromH, C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),NR^(a)R^(a), N(R^(a))C(═O)(C I-alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹³ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkyNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹³ isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),NR^(a)R^(a), N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆ alkylOR^(a).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹³ is H.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹³ is independently, at each instance, selected fromC₁₋₈alkyl, cyano, nitro, —C(═O)(C₁₋₈alkyl), —C(═O)O(C₁₋₈alkyl),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)(C₁₋₈alkyl),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl),—S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a)—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹³ is a saturated or unsaturated 5-, 6- or7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclicring containing 1, 2 or 3 atoms selected from N, O and S, wherein thering is fused with 0 or 1 benzo groups and 0 or 1 saturated orunsaturated 5-, 6- or 7-membered heterocyclic ring containing 1, 2 or 3atoms selected from N, O and S; wherein the carbon atoms of the ring aresubstituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by0, 1, 2 or 3 groups selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)(C₁₋₈alkyl), —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹³ is C₁₋₄alkyl substituted by 0, 1, 2 or 3 groupsselected from C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹⁴ is independently, at each instance, selected fromH, C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁴ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆-alkylOR^(a); or R¹⁴ isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹⁴ is H.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹⁴ is independently, at each instance, selected fromC₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁴ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁴ isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a), —SR^(a),—S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any one of the above andbelow embodiments, at least one of R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ is otherthan H. In another embodiment, in conjunction with any one of the aboveand below embodiments, at least two of R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ isother than H.

R^(a) is independently, at each instance, H, phenyl, benzyl orC₁₋₆alkyl;

R^(b) is a heterocycle selected from the group of thiophene, pyrrole,1,3-oxazole, 1,3-thiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole,1,2,3-oxadiazole, 1,2,3-thiadiazole, 1H-1,2,3-triazole, isothiazole,1,2,4-oxadiazole, 1,2,4-thiadiazole, 1,2,3,4-oxatriazole,1,2,3,4-thiatriazole, 1H-1,2,3,4-tetraazole, 1,2,3,5-oxatriazole,1,2,3,5-thiatriazole, furan, imidazol-1-yl, imidazol-4-yl,1,2,4-triazol-4-yl, 1,2,4-triazol-5-yl, isoxazol-3-yl, isoxazol-5-yl,pyrazol-3-yl, pyrazol-5-yl, thiolane, pyrrolidine, tetrahydrofuran,4,5-dihydrothiophene, 2-pyrroline, 4,5-dihydrofuran, pyridazine,pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,2,4-triazine,1,3,5-triazine, pyridine, 2H-3,4,5,6-tetrahydropyran, thiane,1,2-diazaperhydroine, 1,3-diazaperhydroine, piperazine,1,3-oxazaperhydroine, morpholine, 1,3-thiazaperhydroine,1,4-thiazaperhydroine, piperidine, 2H-3,4-dihydropyran,2,3-dihydro-4H-thiin, 1,4,5,6-tetrahydropyridine, 2H-5,6-dihydropyran,2,3-dihydro-6H-thiin, 1,2,5,6-tetrahydropyridine,3,4,5,6-tetrahydropyridine, 4H-pyran, 4H-thiin, 1,4-dihydropyridine,1,4-dithiane, 1,4-dioxane, 1,4-oxathiane, 1,2-oxazolidine,1,2-thiazolidine, pyrazolidine, 1,3-oxazolidine, 1,3-thiazolidine,imidazolidine, 1,2,4-oxadiazolidine, 1,3,4-oxadiazolidine,1,2,4-thiadiazolidine, 1,3,4-thiadiazolidine, 1,2,4-triazolidine,2-imidazoline, 3-imidazoline, 2-pyrazoline, 4-imidazoline,2,3-dihydroisothiazole, 4,5-dihydroisoxazole, 4,5-dihydroisothiazole,2,5-dihydroisoxazole, 2,5-dihydroisothiazole, 2,3-dihydroisoxazole,4,5-dihydrooxazole, 2,3-dihydrooxazole, 2,5-dihydrooxazole,4,5-dihydrothiazole, 2,3-dihydrothiazole, 2,5-dihydrothiazole,1,3,4-oxathiazolidine, 1,4,2-oxathiazolidine,2,3-dihydro-1H-[1,2,3]triazole, 2,5-dihydro-1H-[1,2,3]triazole,4,5-dihydro-1H-[1,2,3]triazole, 2,3-dihydro-1H-[1,2,4]triazole,4,5-dihydro-1H-[1,2,4]triazole, 2,3-dihydro-[1,2,4]oxadiazole,2,5-dihydro-[1,2,4]oxadiazole, 4,5-dihydro-[1,2,4]thiadiazole,2,3-dihydro-[1,2,4] thidiazole, 2,5-dihydro-[1,2,4] thiadiazole,4,5-dihydro-[1,2,4] thiadiazole, 2,5-dihydro-[1,2,4]oxadiazole,2,3-dihydro-[1,2,4]oxadiazole, 4,5-dihydro-[1,2,4]oxadiazole,2,5-dihydro-[1,2,4]thiadiazole, 2,3-dihydro-[1,2,4] thiadiazole,4,5-dihydro-[1,2,4] thiadiazole, 2,3-dihydro-[1,3,4]oxadiazole,2,3-dihydro-[1,3,4]thiadiazole, [1,4,2]oxathiazole, [1,3,4]oxathiazole,1,3,5-triazaperhydroine, 1,2,4-triazaperhydroine,1,4,2-dithiazaperhydroine, 1,4,2-dioxazaperhydroine,1,3,5-oxadiazaperhydroine, 1,2,5-oxadiazaperhydroine,1,3,4-thiadiazaperhydroine, 1,3,5-thiadiazaperhydroine,1,2,5-thiadiazaperhydroine, 1,3,4-oxadiazaperhydroine,1,4,3-oxathiazaperhydroine, 1,4,2-oxathiazaperhydroine,1,4,5,6-tetrahydropyridazine, 1,2,3,4-tetrahydropyridazine,1,2,3,6-tetrahydropyridazine, 1,2,5,6-tetrahydropyrimidine,1,2,3,4-tetrahydropyrimidine, 1,4,5,6-tetrahydropyrimidine,1,2,3,6-tetrahydropyrazine, 1,2,3,4-tetrahydropyrazine,5,6-dihydro-4H-[1,2]oxazine, 5,6-dihydro-2H-[1,2]oxazine,3,6-dihydro-2H-[1,2]oxazine, 3,4-dihydro-2H-[1,2]oxazine,5,6-dihydro-4H-[1,2]thiazine, 5,6-dihydro-2H-[1,2] thiazine,3,6-dihydro-2H-[1,2] thiazine, 3,4-dihydro-2H-[1,2] thiazine,5,6-dihydro-2H-[1,3]oxazine, 5,6-dihydro-4H-[1,3]oxazine,3,6-dihydro-2H-[1,3]oxazine, 3,4dihydro-2H-[1,3]oxazine,3,6-dihydro-2H-[1,4]oxazine, 3,4-dihydro-2H-[1,4]oxazine,5,6-dihydro-2H-[1,3]thiazine, 5,6-dihydro-4H-[1,3]thiazine,3,6-dihydro-2H-[1,3]thiazine, 3,4-dihydro-2H-[1,3]thiazine,3,6-dihydro-2H-[1,4]thiazine, 3,4-dihydro-2H-[1,4]thiazine,1,2,3,6-tetrahydro-[1,2,4]triazine, 1,2,3,4-tetrahydro-[1,2,4]triazine,1,2,3,4-tetrahydro-[1,3,5]triazine, 2,3,4,5-tetrahydro-[1,2,4]triazine,1,4,5,6-tetrahydro-[1,2,4]triazine, 5,6-dihydro-[1,4,2]dioxazine,5,6-dihydro-[1,4,2]dioxazine, 5,6-dihydro-[1,4,2]dithiazine,2,3-dihydro-[1,4,2]dioxazine, 3,4-dihydro-2H-[1,3,4]oxadiazine,3,6-dihydro-2H-[1,3,4]oxadiazine, 3,4-dihydro-2H-[1,3,5]oxadiazine,3,6-dihydro-2H-[1,3,5]oxadiazine, 5,6-dihydro-2H-[1,2,5]oxadiazine,5,6-dihydro-4H-[1,2,5]oxadiazine, 3,4-dihydro-2H-[1,3,4]thiadiazine,3,6-dihydro-2H-[1,3,4]thiadiazine, 3,4-dihydro-2H-[1,3,5]thiadiazine,3,6-dihydro-2H-[1,3,5]thiadiazine, 5,6-dihydro-2H-[1,2,5]thiadiazine,5,6-dihydro-4H-[1,2,5]thiadiazine, 5,6-dihydro-2H-[1,2,3]oxadiazine,3,6-dihydro-2H-[1,2,5]oxadiazine, 5,6-dihydro-4H-[1,3,4]oxadiazine,3,4-dihydro-2H-[1,2,5]oxadiazine, 5,6-dihydro-2H-[1,2,3]thiadiazine,3,6-dihydro-2H-[1,2,5]thiadiazine, 5,6-dihydro-4H-[1,3,4]thiadiazine,3,4-dihydro-2H-[1,2,5]thiadiazine, 5,6-dihydro-[1,4,3]oxathiazine,5,6-dihydro-[1,4,2]oxathiazine, 2,3-dihydro-[1,4,3]oxathiazine,2,3-dihydro-[1,4,2]oxathiazine, 4,5-dihydropyridine,1,6-dihydropyridine, 5,6-dihydropyridine, 2H-pyran, 2H-thiin,3,6-dihydropyridine, 2,3-dihydropyridazine, 2,5-dihydropyridazine,4,5-dihydropyridazine, 1,2-dihydropyridazine, 2,3-dihydropyrimidine,2,5-dihydropyrimidine, 5,6-dihydropyrimidine, 3,6-dihydropyrimidine,4,5-dihydropyrazine, 5,6-dihydropyrazine, 3,6-dihydropyrazine,4,5-dihydropyrazine, 1,4-dihydropyrazine, 1,4-dithiin, 1,4-dioxin,2H-1,2-oxazine, 6H-1,2-oxazine, 4H-1,2-oxazine, 2H-1,3-oxazine,4H-1,3-oxazine, 6H-1,3-oxazine, 2H-1,4-oxazine, 4H-1,4-oxazine,2H-1,3-thiazine, 2H-1,4-thiazine, 4H-1,2-thiazine, 6H-1,3-thiazine,4H-1,4-thiazine, 2H-1,2-thiazine, 6H-1,2-thiazine, 1,4-oxathiin,2H,5H-1,2,3-triazine, 1H,4H-1,2,3-triazine, 4,5-dihydro-1,2,3-triazine,1H,6H-1,2,3-triazine, 1,2-dihydro-1,2,3-triazine,2,3-dihydro-1,2,4-triazine, 3H,6H-1,2,4-triazine, 1H,6H-1,2,4-triazine,3,4-dihydro-1,2,4-triazine, 1H,4H-1,2,4-triazine,5,6-dihydro-1,2,4-triazine, 4,5-dihydro-1,2,4-triazine,2H,5H-1,2,4-triazine, 1,2dihydro-1,2,4-triazine, 1H,4H-1,3,5-triazine,1,2-dihydro-1,3,5-triazine, 1,4,2-dithiazine, 1,4,2-dioxazine,2H-1,3,4-oxadiazine, 2H-1,3,5-oxadiazine, 6H-1,2,5-oxadiazine,4H-1,3,4-oxadiazine, 4H-1,3,5-oxadiazine, 4H-1,2,5-oxadiazine,2H-1,3,5-thiadiazine, 6H-1,2,5-thiadiazine, 4H-1,3,4-thiadiazine,4H-1,3,5-thiadiazine, 4H-1,2,5-thiadiazine, 2H-1,3,4-thiadiazine,6H-1,3,4-thiadiazine, 6H-1,3,4-oxadiazine and 1,4,2-oxathiazine, whereinthe heterocycle is optionally vicinally fused with a saturated orunsaturated 5-, 6- or 7-membered ring containing 0, 1 or 2 atomsindependently selected from N, O and S;

-   -   R^(c) is independently, in each instance, phenyl substituted by        0, 1 or 2 groups selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl,        —OR^(a) and —NR^(a)R^(a); or R^(c) is a saturated or unsaturated        5- or 6-membered ring heterocycle containing 1, 2 or 3        heteroatoms independently selected from N, O and S, wherein no        more than 2 of the ring members are O or S, wherein the        heterocycle is optionally fused with a phenyl ring, and the        carbon atoms of the heterocycle are substituted by 0, 1 or 2 oxo        groups, wherein the heterocycle or fused phenyl ring is        substituted by 0, 1, 2 or 3 substituents selected from halo,        C₁₋₄alkyl, C₁₋₃haloalkyl, —OR^(a) and —NR^(a)R^(a);    -   R^(d) is hydrogen or —CH₃;    -   R^(e) is, independently, in each instance, C₁₋₈alkyl substituted        by 0, 1, 2, 3 or 4 substituents selected from halo, cyano,        nitro, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),        —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),        —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),        —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        NR^(a)R^(a), N(R^(a))C(═O)R^(b), N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); and        wherein the C₁₋₈alkyl is additionally substituted by 0 or 1        groups independently selected from R^(g);    -   R^(f) is, independently, in each instance, R^(e) or H; and    -   R^(g) is, independently, in each instance, a saturated or        unsaturated 5- or 6-membered monocyclic ring containing 1, 2 or        3 atoms selected from N, O and S, so long as the combination of        O and S atoms is not greater than 2, wherein the carbon atoms of        the ring are substituted by 0 or 1 oxo groups.

As stated above, the above embodiments and sub-embodiments may be usedin conjuction with other embodiments and subembodiments listed. Thefollowing table is a non-exclusive, non-limiting list of some of thecombinations of embodiments. Although the following embodiment sets aremeant to be used with any of the above embodiments, they are alsoconsidered wherein R⁵, R⁶, R⁸, R¹³ and R¹⁴ are all H.

Where X is ═N— and Y is —CH—: Emb. # R¹ R⁴ R⁷ R⁹ R¹⁰ R¹¹ R¹² 1001 C E —— N N Q 1002 C E — — O O Q 1003 C E — — P P Q 1004 C E — — M R R 1005 CE — — M S S 1006 C E — — M T T 1007 C D — — — — — 1008 C F — — — — —1009 C G — — — — — 1010 A E H J N N Q 1011 A E H J O O Q 1012 A E H J PP Q 1013 A E H J M R R 1014 A E H J M S S 1015 A E H J M T T 1016 A D HJ — — — 1017 A F H J — — — 1018 A G H J — — — 1019 A E H K N N Q 1020 AE H K O O Q 1021 A E H K P P Q 1022 A E H K M R R 1023 A E H K M S S1024 A E H K M T T 1025 A D H K — — — 1026 A F H K — — — 1027 A G H K —— — 1028 A E H L N N Q 1029 A E H L O O Q 1030 A E H L P P Q 1031 A E HL M R R 1032 A E H L M S S 1033 A E H L M T T 1034 A D H L — — — 1035 AF H L — — — 1036 A G H L — — — 1037 A E I J N N Q 1038 A E I J O O Q1039 A E I J P P Q 1040 A E I J M R R 1041 A E I J M S S 1042 A E I J MT T 1043 A D I J — — — 1044 A F I J — — — 1045 A G I J — — — 1046 A E IK N N Q 1047 A E I K O O Q 1048 A E I K P P Q 1049 A E I K M R R 1050 AE I K M S S 1051 A E I K M T T 1052 A D I K — — — 1053 A F I K — — —1054 A G I K — — — 1055 A E I L N N Q 1056 A E I L O O Q 1057 A E I L PP Q 1058 A E I L M R R 1059 A E I L M S S 1060 A E I L M T T 1061 A D IL — — — 1062 A F I L — — — 1063 A G I L — — — 1064 B E H J N N Q 1065 BE H J O O Q 1066 B E H J P P Q 1067 B E H J M R R 1068 B E H J M S S1069 B E H J M T T 1070 B D H J — — — 1071 B F H J — — — 1072 B G H J —— — 1073 B E H K N N Q 1074 B E H K O O Q 1075 B E H K P P Q 1076 B E HK M R R 1077 B E H K M S S 1078 B E H K M T T 1079 B D H K — — — 1080 BF H K — — — 1081 B G H K — — — 1082 B E H L N N Q 1083 B E H L O O Q1084 B E H L P P Q 1085 B E H L M R R 1086 B E H L M S S 1087 B E H L MT T 1088 B D H L — — — 1089 B F H L — — — 1090 B G H L — — — 1091 B E IJ N N Q 1092 B E I J O O Q 1093 B E I J P P Q 1094 B E I J M R R 1095 BE I J M S S 1096 B E I J M T T 1097 B D I J — — — 1098 B F I J — — —1099 B G I J — — — 1100 B E I K N N Q 1101 B E I K O O Q 1102 B E I K PP Q 1103 B E I K M R R 1104 B E I K M S S 1105 B E I K M T T 1106 B D IK — — — 1107 B F I K — — — 1108 B G I K — — — 1109 B E I L N N Q 1110 BE I L O O Q 1111 B E I L P P Q 1112 B E I L M R R 1113 B E I L M S S1114 B E I L M T T 1115 B D I L — — — 1116 B F I L — — — 1117 B G I L —— —

Where X is —CH— and Y is ═N—: Emb. # R¹ R⁴ R⁷ R⁹ R¹⁰ R¹¹ R¹² 2001 C E —— N N Q 2002 C E — — O O Q 2003 C E — — P P Q 2004 C E — — M R R 2005 CE — — M S S 2006 C E — — M T T 2007 C D — — — — — 2008 C F — — — — —2009 C G — — — — — 2010 A E H J N N Q 2011 A E H J O O Q 2012 A E H J PP Q 2013 A E H J M R R 2014 A E H J M S S 2015 A E H J M T T 2016 A D HJ — — — 2017 A F H J — — — 2018 A G H J — — — 2019 A E H K N N Q 2020 AE H K O O Q 2021 A E H K P P Q 2022 A E H K M R R 2023 A E H K M S S2024 A E H K M T T 2025 A D H K — — — 2026 A F H K — — — 2027 A G H K —— — 2028 A E H L N N Q 2029 A E H L O O Q 2030 A E H L P P Q 2031 A E HL M R R 2032 A E H L M S S 2033 A E H L M T T 2034 A D H L — — — 2035 AF H L — — — 2036 A G H L — — — 2037 A E I J N N Q 2038 A E I J O O Q2039 A E I J P P Q 2040 A E I J M R R 2041 A E I J M S S 2042 A E I J MT T 2043 A D I J — — — 2044 A F I J — — — 2045 A G I J — — — 2046 A E IK N N Q 2047 A E I K O O Q 2048 A E I K P P Q 2049 A E I K M R R 2050 AE I K M S S 2051 A E I K M T T 2052 A D I K — — — 2053 A F I K — — —2054 A G I K — — — 2055 A E I L N N Q 2056 A E I L O O Q 2057 A E I L PP Q 2058 A E I L M R R 2059 A E I L M S S 2060 A E I L M T T 2061 A D IL — — — 2062 A F I L — — — 2063 A G I L — — — 2064 B E H J N N Q 2065 BE H J O O Q 2066 B E H J P P Q 2067 B E H J M R R 2068 B E H J M S S2069 B E H J M T T 2070 B D H J — — — 2071 B F H J — — — 2072 B G H J —— — 2073 B E H K N N Q 2074 B E H K O O Q 2075 B E H K P P Q 2076 B E HK M R R 2077 B E H K M S S 2078 B E H K M T T 2079 B D H K — — — 2080 BF H K — — — 2081 B G H K — — — 2082 B E H L N N Q 2083 B E H L O O Q2084 B E H L P P Q 2085 B E H L M R R 2086 B E H L M S S 2087 B E H L MT T 2088 B D H L — — — 2089 B F H L — — — 2090 B G H L — — — 2091 B E IJ N N Q 2092 B E I J O O Q 2093 B E I J P P Q 2094 B E I J M R R 2095 BE I J M S S 2096 B E I J M T T 2097 B D I J — — — 2098 B F I J — — —2099 B G I J — — — 2100 B E I K N N Q 2101 B E I K O O Q 2102 B E I K PP Q 2103 B E I K M R R 2104 B E I K M S S 2105 B E I K M T T 2106 B D IK — — — 2107 B F I K — — — 2108 B G I K — — — 2109 B E I L N N Q 2110 BE I L O O Q 2111 B E I L P P Q 2112 B E I L M R R 2113 B E I L M S S2114 B E I L M T T 2115 B D I L — — — 2116 B F I L — — — 2117 B G I L —— —

Another aspect of the current invention relates to compounds having thegeneral structure:

or any pharmaceutically-acceptable salt thereof, wherein:

-   -   X is ═N— or ═C(R²)—;    -   Y is ═N— or ═C(R³)—, wherein at least one of X and Y is not ═N—;    -   n is independently, at each instance, 0, 1 or 2.    -   R¹ is    -    or R¹ is a naphthyl substituted by 0, 1, 2 or 3 substituents        independently selected from R⁵; or R¹ is R^(b) substituted by 1,        2 or 3 substituents independently selected from R⁵;    -   R² is, independently, in each instance, R¹⁰, C₁₋₈alkyl        substituted by 0, 1 or 2 substituents selected from R¹⁰,        —(CH₂)_(n)phenyl substituted by 0, 1, 2 or 3 substitutents        independently selected from R¹⁰, or a saturated or unsaturated        5- or 6-membered ring heterocycle containing 1, 2 or 3        heteroatoms independently selected from N, O and S, wherein no        more than 2 of the ring members are O or S, wherein the        heterocycle is optionally fused with a phenyl ring, and the        heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3        substituents independently selected from R¹⁰;    -   R³ is, independently, in each instance, H, halo, —NH₂,        —NHC₁₋₃alkyl, —N(C₁₋₃alkyl)C₁₋₃alkyl, or C₁₋₃alkyl;    -   R⁴ is    -    or    -    R⁴ is a saturated or unsaturated 5- or 6-membered ring        heterocycle containing 1, 2 or 3 atoms selected from O, N and S        that is optionally vicinally fused with a saturated or        unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms        selected from O, N and S with the remaining atoms being carbon,        so long as the combination of O and S atoms is not greater than        2, wherein the carbon atoms of the heterocycle and bridge are        substituted by 0, 1, 2 or 3 substituents independently selected        from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, nitro, cyano, oxo, —OR^(a),        —S(═O)_(n)C₁₋₆alkyl, —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —OC₁₋₆alkyl(═O)_(n)OR^(a), —NR^(a)R^(a),        —NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂ alkylNR^(a)R^(a),        —NR^(a)C₂₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,        —OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl and        —NR^(a)C(═O)C₁₋₆alkyl; and unsaturated carbon atoms may be        additionally substituted by ═O; and any nitrogen atoms in the        chain are substituted by H, —C₁₋₆alkylOR^(a)R^(a), —C₁₋₆alkyl,        —C₁₋₆alkylNR^(a)R^(a), —C₁₋₃alkylC(═O)OR^(a),        —C₁₋₃alkylC(═O)NR^(a)R^(a), —C₁₋₃alkylOC(═O)C₁₋₆alkyl,        —C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(c) or —C₁₋₃alkylR^(c);        or R⁴ is 10-membered bicyclic ring comprising fused 6-membered        rings, containing 0, 1, 2, 3 or 4 N atoms with the remainder        being carbon atoms, with at least one of the 6-membered rings        being aromatic, wherein the carbon atoms are substituted by H,        halo, OR^(a), NR^(a)R^(a), C₁₋₆alkyl and C₁₋₃haloalkyl; and        unsaturated carbon atoms may be additionally substituted by ═O;        but in no instance is R⁴ 3,5-ditrifluoromethylphenyl or        3-trifluoromethyl-4-fluorophenyl;    -   R⁵ is independently, at each instance, H, C₁₋₅alkyl,        C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a),        —NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a),        —NR^(a)C₂₋₆alkylOR^(a), naphthyl, —CO₂(C₁₋₆alkyl),        —C(═O)(C₁₋₆alkyl), —C(═O)NR^(a)R^(a), —NR^(a)C(═O)R^(a),        —NR^(a)C(═O)NR^(a)R^(a), —NR^(a)CO₂(C₁₋₆alkyl),        —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a), —S(═O)_(n)(C₁₋₆alkyl),        —S(═O)₂NR^(a)R^(a), —NR^(a)S(═O)₂(C₁₋₆alkyl),        —OC(═O)NR^(a)R^(a), a phenyl ring substituted with 0, 1, 2, or 3        substituents independently selected from R¹⁰; or R⁵ is a        saturated or unsaturated 5- or 6-membered ring heterocycle        containing 1, 2 or 3 atoms selected from O, N and S, substituted        with 0, 1, 2, or 3 substituents independently selected from R¹⁰;    -   R⁶ is independently, at each instance, H, C₁₋₅alkyl,        C₁₋₄haloalkyl, halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a),        —NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a) or        —NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a),        —S(C₁₋₆alkyl), a phenyl ring substituted with 1, 2, or 3        substituents independently selected from R¹⁰; or R⁶ is a        saturated or unsaturated 5- or 6-membered ring heterocycle        containing 1, 2 or 3 atoms selected from O, N and S substituted        with 0, 1, 2, or 3 substituents independently selected from R¹⁰;    -   R⁷ is independently, at each instance, H, C₁₋₈alkyl,        C₁₋₄haloalkyl, halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a),        —NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a),        —NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a)        or —S(C₁₋₆alkyl); or R⁷ is a saturated or unsaturated 4- or        5-membered ring heterocycle containing a single nitrogen atom,        wherein the ring is substituted with 0, 1 or 2 substituents        independently selected from halo, C₁₋₂haloalkyl and C₁₋₃alkyl;    -   R⁸ is independently, at each instance, H, C₁₋₅alkyl,        C₁₋₄haloalkyl, halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl, —OC₂₋₆alkyl        NR^(a)R^(a), —NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a),        —NR^(a)C₂₋₆ alkylOR^(a), —C₁₋₈-alkylOR^(a),        —C₁₋₆alkylNR^(a)R^(a), —S(C₁₋₆alkyl), a phenyl ring substituted        with 1, 2, or 3 substituents independently selected from R¹⁰, or        R⁸ is a saturated or unsaturated 5- or 6-membered ring        heterocycle containing 1, 2 or 3 atoms selected from O, N and S        substituted with 0, 1, 2, or 3 substituents independently        selected from R¹⁰;    -   R⁹ is independently, at each instance, H, C₁₋₈alkyl,        C₁₋₄haloalkyl, halo, nitro, cyano, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a),        —NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a) or        —NR^(a)C₂₋₆alkylOR^(a), —CO₂(C₁₋₆alkyl), —C(═O)(C₁₋₆alkyl),        —C(═O)NR^(a)R^(a), —NR^(a)C(═O)(C₁₋₆alkyl),        —NR^(a)C(═O)NR^(a)R^(a), —NR^(a)CO₂(C₁₋₆alkyl),        —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a), —S(═O)_(n)(C₁₋₆alkyl),        —S(═O)₂NR^(a)R^(a), —NR^(a)S(═O)₂(C₁₋₆alkyl),        —OC(═O)NR^(a)R^(a), a phenyl ring substituted with 0, 1, 2, or 3        substituents independently selected from R¹⁰; or R⁹ is a        saturated or unsaturated 5- or 6-membered ring heterocycle        containing 1, 2 or 3 atoms selected from O, N and S substituted        with 0, 1, 2, or 3 substituents independently selected from R¹⁰;        wherein at least one of R⁵, R⁶, R⁷, R⁸ and R⁹ is C₁₋₈alkyl,        C₁₋₄haloalkyl, halo, —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —NR^(a)C₁₋₄haloalkyl, or —S(C₁₋₆alkyl); or R⁹        is a saturated or unsaturated 4- or 5-membered ring heterocycle        containing a single nitrogen atom, wherein the ring is        substituted with 0, 1 or 2 substituents independently selected        from halo, C₁₋₂haloalkyl and C₁₋₃alkyl;    -   R¹⁰ is independently, at each instance, selected from H,        C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),        —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl),        —S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a),        —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),        —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),        —N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁰        is a saturated or unsaturated 5-, 6- or 7-membered monocyclic or        6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 1, 2        or 3 atoms selected from N, O and S, wherein the ring is fused        with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5-,        6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms        selected from N, O and S; wherein the carbon atoms of the ring        are substituted by 0, 1 or 2 oxo groups, wherein the ring is        substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,        C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),        —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl),        —S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a),        —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)(C        18alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl), —N(R^(a))C(═O)NR^(a)R^(a),        —N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂(C₁₋₈alkyl),        —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and        —NR^(a)C₂ alkylOR^(a); or R¹⁰ is C₁₋₄alkyl substituted by 0, 1,        2 or 3 groups selected from C₁₋₄haloalkyl, halo, cyano, nitro,        —C(═O)(C₁₋₈alkyl), —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a),        —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)(C₁₋₈alkyl),        —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a),        —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a),        —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),        —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);    -   R¹¹ is independently, at each instance, selected from H,        C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),        —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl),        —S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a),        —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),        —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹¹        is a saturated or unsaturated 5-, 6- or 7-membered monocyclic or        6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 1, 2        or 3 atoms selected from N, O and S, wherein the ring is fused        with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5-,        6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms        selected from N, O and S; wherein the carbon atoms of the ring        are substituted by 0, 1 or 2 oxo groups, wherein the ring is        substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,        C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),        —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)(C₁₋₈ alkyl), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl),        —S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a),        —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),        —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),        NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹¹ is        C₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected from        C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),        —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), SR^(a), —S(═O)(C₁₋₈alkyl),        —S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a),        —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),        —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁰        and R¹¹ together are a saturated or unsaturated 3- or 4-atom        bridge containing 0, 1, 2 or 3 atoms selected from O, N and S        with the remaining atoms being carbon, so long as the        combination of O and S atoms is not greater than 2, wherein the        each of the carbon atoms in the chain is substituted by H, ═O,        C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),        —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl),        —S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a),        —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),        —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a), and any        nitrogen atoms in the chain are substituted by H,        —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a),        —C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a),        —C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl,        —C(═O)R^(c) or —C₁₋₃alkylR^(c);    -   R¹² is independently, at each instance, selected from H,        C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),        —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a), —OC₂        alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),        —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),        —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹² is a        saturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-,        7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 1, 2 or        3 atoms selected from N, O and S, wherein the ring is fused with        0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5-, 6-        or 7-membered heterocyclic ring containing 1, 2 or 3 atoms        selected from N, O and S; wherein the carbon atoms of the ring        are substituted by 0, 1 or 2 oxo groups, wherein the ring is        substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,        C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),        —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl),        —S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a),        —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),        —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹²        is C₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected from        C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),        —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl),        —S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a),        —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),        —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); wherein        if R¹¹ or R¹³ is CF₃, then R¹² is not F; or R¹¹ and R¹² together        are a saturated or unsaturated 3- or 4-atom bridge containing 0,        1, 2 or 3 atoms selected from O, N and S with the remaining        atoms being carbon, so long as the combination of O and S atoms        is not greater than 2, wherein the each of the carbon atoms in        the chain is substituted by H, ═O, C₁₋₈alkyl, C₁₋₄haloalkyl,        halo, cyano, nitro, —C(═O)(C₁₋₈alkyl), —C(═O)O(C₁₋₈alkyl),        —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),        —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),        —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),        —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),        —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a), and any        nitrogen atoms in the chain are substituted by H,        —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a),        —C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a),        —C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl,        —C(═O)R^(c) or —C₁₋₃alkylR^(c);    -   R¹³ is independently, at each instance, selected from H,        C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),        —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl),        —S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a),        —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),        —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂alkylOR^(a); or R¹³ is        a saturated or unsaturated 5-, 6- or 7-membered monocyclic or        6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 1, 2        or 3 atoms selected from N, O and S, wherein the ring is fused        with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5-,        6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms        selected from N, O and S; wherein the carbon atoms of the ring        are substituted by 0, 1 or 2 oxo groups, wherein the ring is        substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,        C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),        —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl),        —S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a),        —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),        —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂ alkylOR^(a); or R¹³ is        C₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected from        C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),        —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl),        —S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a), —S(═O)₂        S(═O)₂NR^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl),        —N(R^(a))C(═O)O(C₁₋₈alkyl), —N(R^(a))C(═O)NR^(a)R^(a),        —N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂(C₁₋₈alkyl),        —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and        —NR²⁻⁶ alkylOR^(a);    -   R¹⁴ is independently, at each instance, selected from H,        C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),        —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl),        —S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a),        —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),        N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁴        is a saturated or unsaturated 5-, 6- or 7-membered monocyclic or        6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 1, 2        or 3 atoms selected from N, O and S, wherein the ring is fused        with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 5-,        6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms        selected from N, O and S; wherein the carbon atoms of the ring        are substituted by 0, 1 or 2 oxo groups, wherein the ring is        substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,        C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),        —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl),        —S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a),        —S(═O)₂N(R^(a))C(═O)(C₁alkyl), —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),        —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a)        —N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁴        is C₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected from        C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),        —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),        —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a),        —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),        —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),        —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);    -   R^(a) is independently, at each instance, H, phenyl, benzyl or        C₁₋₆alkyl;    -   R^(b) is a heterocycle selected from the group of thiophene,        pyrrole, 1,3-oxazole, 1,3-thiazole, 1,3,4-oxadiazole,        1,3,4-thiadiazole, 1,2,3-oxadiazole, 1,2,3-thiadiazole,        1H-1,2,3-triazole, isothiazole, 1,2,4-oxadiazole,        1,2,4-thiadiazole, 1,2,3,4-oxatriazole, 1,2,3,4-thiatriazole,        1H-1,2,3,4-tetraazole, 1,2,3,5-oxatriazole,        1,2,3,5-thiatriazole, furan, imidazol-1-yl, imidazol-4-yl,        1,2,4-triazol-4-yl, 1,2,4-triazol-5-yl, isoxazol-3-yl,        isoxazol-5-yl, pyrazol-3-yl, pyrazol-5-yl, thiolane,        pyrrolidine, tetrahydrofuran, 4,5-dihydrothiophene, 2-pyrroline,        4,5-dihydrofuran, pyridazine, pyrimidine, pyrazine,        1,2,3-triazine, 1,2,4-triazine, 1,2,4-triazine, 1,3,5-triazine,        pyridine, 2H-3,4,5,6-tetrahydropyran, thiane,        1,2diazaperhydroine, 1,3-diazaperhydroine, piperazine,        1,3-oxazaperhydroine, morpholine, 1,3-thiazaperhydroine,        1,4-thiazaperhydroine, piperidine, 2H-3,4-dihydropyran,        2,3-dihydro-4H-thiin, 1,4,5,6-tetrahydropyridine,        2H-5,6-dihydropyran, 2,3-dihydro-6H-thiin,        1,2,5,6-tetrahydropyridine, 3,4,5,6-tetrahydropyridine,        4H-pyran, 4H-thiin, 1,4-dihydropyridine, 1,4-dithiane,        1,4-dioxane, 1,4-oxathiane, 1,2-oxazolidine, 1,2-thiazolidine,        pyrazolidine, 1,3-oxazolidine, 1,3-thiazolidine, imidazolidine,        1,2,4-oxadiazolidine, 1,3,4-oxadiazolidine,        1,2,4-thiadiazolidine, 1,3,4-thiadiazolidine,        1,2,4-triazolidine, 2-imidazoline, 3-imidazoline, 2-pyrazoline,        4-imidazoline, 2,3-dihydroisothiazole, 4,5-dihydroisoxazole,        4,5-dihydroisothiazole, 2,5-dihydroisoxazole,        2,5-dihydroisothiazole, 2,3-dihydroisoxazole,        4,5-dihydrooxazole, 2,3-dihydrooxazole, 2,5-dihydrooxazole,        4,5-dihydrothiazole, 2,3-dihydrothiazole, 2,5-dihydrothiazole,        1,3,4-oxathiazolidine, 1,4,2-oxathiazolidine,        2,3-dihydro-1H-[1,2,3]triazole, 2,5-dihydro-1H-[1,2,3]triazole,        4,5-dihydro-1H-[1,2,3]triazole, 2,3-dihydro-1H-[1,2,4]triazole,        4,5-dihydro-1H-[1,2,4]triazole, 2,3-dihydro-[1,2,4]oxadiazole,        2,5-dihydro-[1,2,4]oxadiazole, 4,5-dihydro-[1,2,4]thiadiazole,        2,3-dihydro-[1,2,4] thidiazole, 2,5-dihydro-[1,2,4] thiadiazole,        4,5-dihydro-[1,2,4] thiadiazole, 2,5-dihydro-[1,2,4]oxadiazole,        2,3-dihydro-[1,2,4]oxadiazole, 4,5-dihydro-[1,2,4]oxadiazole,        2,5-dihydro-[1,2,4]thiadiazole, 2,3-dihydro-[1,2,4] thiadiazole,        4,5-dihydro-[1,2,4] thiadiazole, 2,3-dihydro-[1,3,4]oxadiazole,        2,3-dihydro-[1,3,4]thiadiazole, [1,4,2]oxathiazole,        [1,3,4]oxathiazole, 1,3,5-triazaperhydroine,        1,2,4-triazaperhydroine, 1,4,2-dithiazaperhydroine,        1,4,2-dioxazaperhydroine, 1,3,5-oxadiazaperhydroine,        1,2,5-oxadiazaperhydroine, 1,3,4-thiadiazaperhydroine,        1,3,5-thiadiazaperhydroine, 1,2,5-thiadiazaperhydroine,        1,3,4-oxadiazaperhydroine, 1,4,3-oxathiazaperhydroine,        1,4,2-oxathiazaperhydroine, 1,4,5,6-tetrahydropyridazine,        1,2,3,4-tetrahydropyridazine, 1,2,3,6-tetrahydropyridazine,        1,2,5,6-tetrahydropyrimidine, 1,2,3,4-tetrahydropyrimidine,        1,4,5,6-tetrahydropyrimidine, 1,2,3,6-tetrahydropyrazine,        1,2,3,4-tetrahydropyrazine, 5,6-dihydro-4H-[1,2]oxazine,        5,6-dihydro-2H-[1,2]oxazine, 3,6-dihydro-2H-[1,2]oxazine,        3,4-dihydro-2H-[1,2]oxazine, 5,6-dihydro-4H-[1,2]thiazine,        5,6-dihydro-2H-[1,2] thiazine, 3,6-dihydro-2H-[1,2] thiazine,        3,4-dihydro-2H-[1,2] thiazine, 5,6-dihydro-2H-[1,3]oxazine,        5,6-dihydro-4H-[1,3]oxazine, 3,6-dihydro-2H-[1,3]oxazine,        3,4-dihydro-2H-[1,3]oxazine, 3,6-dihydro-2H-[1,4]oxazine,        3,4-dihydro-2H-[1,4]oxazine, 5,6-dihydro-2H-[1,3]thiazine,        5,6-dihydro-4H-[1,3]thiazine, 3,6-dihydro-2H-[1,3]thiazine,        3,4-dihydro-2H-[1,3]thiazine, 3,6-dihydro-2H-[1,4]thiazine,        3,4-dihydro-2H-[1,4]thiazine,        1,2,3,6-tetrahydro-[1,2,4]triazine,        1,2,3,4-tetrahydro-[1,2,4]triazine,        1,2,3,4-tetrahydro-[1,3,5]triazine,        2,3,4,5-tetrahydro-[1,2,4]triazine,        1,4,5,6-tetrahydro-[1,2,4]triazine,        5,6-dihydro-[1,4,2]dioxazine, 5,6-dihydro-[1,4,2]dioxazine,        5,6-dihydro-[1,4,2]dithiazine, 2,3-dihydro-[1,4,2]dioxazine,        3,4-dihydro-2H-[1,3,4]oxadiazine,        3,6-dihydro-2H-[1,3,4]oxadiazine,        3,4-dihydro-2H-[1,3,5]oxadiazine,        3,6-dihydro-2H-[1,3,5]oxadiazine,        5,6-dihydro-2H-[1,2,5]oxadiazine,        5,6-dihydro-4H-[1,2,5]oxadiazine,        3,4-dihydro-2H-[1,3,4]thiadiazine,        3,6-dihydro-2H-[1,3,4]thiadiazine,        3,4-dihydro-2H-[1,3,5]thiadiazine,        3,6-dihydro-2H-[1,3,5]thiadiazine,        5,6-dihydro-2H-[1,2,5]thiadiazine,        5,6-dihydro-4H-[1,2,5]thiadiazine,        5,6-dihydro-2H-[1,2,3]oxadiazine,        3,6-dihydro-2H-[1,2,5]oxadiazine,        5,6-dihydro-4H-[1,3,4]oxadiazine,        3,4-dihydro-2H-[1,2,5]oxadiazine,        5,6-dihydro-2H-[1,2,3]thiadiazine,        3,6-dihydro-2H-[1,2,5]thiadiazine,        5,6-dihydro-4H-[1,3,4]thiadiazine,        3,4-dihydro-2H-[1,2,5]thiadiazine,        5,6-dihydro-[1,4,3]oxathiazine, 5,6-dihydro-[1,4,2]oxathiazine,        2,3-dihydro-[1,4,3]oxathiazine, 2,3-dihydro-[1,4,2]oxathiazine,        4,5-dihydropyridine, 1,6-dihydropyridine, 5,6-dihydropyridine,        2H-pyran, 2H-thiin, 3,6-dihydropyridine, 2,3-dihydropyridazine,        2,5-dihydropyridazine, 4,5-dihydropyridazine,        1,2-dihydropyridazine, 2,3-dihydropyrimidine,        2,5-dihydropyrimidine, 5,6-dihydropyrimidine,        3,6-dihydropyrimidine, 4,5-dihydropyrazine, 5,6-dihydropyrazine,        3,6-dihydropyrazine, 4,5-dihydropyrazine, 1,4-dihydropyrazine,        1,4-dithiin, 1,4-dioxin, 2H-1,2-oxazine, 6H-1,2-oxazine,        4H-1,2-oxazine, 2H-1,3-oxazine, 4H-1,3-oxazine, 6H-1,3-oxazine,        2H-1,4-oxazine, 4H-1,4-oxazine, 2H-1,3-thiazine,        2H-1,4-thiazine, 4H-1,2-thiazine, 6H-1,3-thiazine,        4H-1,4-thiazine, 2H-1,2-thiazine, 6H-1,2-thiazine, 1,4-oxathiin,        2H,5H-1,2,3-triazine, 1H,4H-1,2,3-triazine,        4,5-dihydro-1,2,3-triazine, 1H,6H-1,2,3-triazine,        1,2-dihydro-1,2,3-triazine, 2,3-dihydro-1,2,4-triazine,        3H,6H-1,2,4-triazine, 1H,6H-1,2,4-triazine,        3,4-dihydro-1,2,4-triazine, 1H,4H-1,2,4-triazine,        5,6-dihydro-1,2,4-triazine, 4,5-dihydro-1,2,4-triazine,        2H,5H-1,2,4-triazine, 1,2-dihydro-1,2,4-triazine,        1H,4H-1,3,5-triazine, 1,2-dihydro-1,3,5-triazine,        1,4,2-dithiazine, 1,4,2-dioxazine, 2H-1,3,4-oxadiazine,        2H-1,3,5-oxadiazine, 6H-1,2,5-oxadiazine, 4H-1,3,4-oxadiazine,        4H-1,3,5-oxadiazine, 4H-1,2,5-oxadiazine, 2H-1,3,5-thiadiazine,        6H-1,2,5-thiadiazine, 4H-1,3,4-thiadiazine,        4H-1,3,5-thiadiazine, 4H-1,2,5-thiadiazine,        2H-1,3,4-thiadiazine, 6H-1,3,4-thiadiazine, 6H-1,3,4-oxadiazine        and 1,4,2-oxathiazine, wherein the heterocycle is optionally        vicinally fused with a saturated or unsaturated 5-, 6- or        7-membered ring containing 0, 1 or 2 atoms independently        selected from N, O and S;

R^(c) is phenyl substituted by 0, 1 or 2 groups selected from halo,C₁₋₄alkyl, C₁₋₃haloalkyl, —OR^(a) and —NR^(a)R^(a); or R^(c) is asaturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein nomore than 2 of the ring members are O or S, wherein the heterocycle isoptionally fused with a phenyl ring, and the carbon atoms of theheterocycle are substituted by 0, 1 or 2 oxo groups, wherein theheterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OR^(a) and—NR^(a)R^(a); and

-   -   R^(d) is hydrogen or —CH₃.

In another embodiment, in conjunction with any one of the above andbelow embodiments, X is ═N—; and either R⁶ is independently, at eachinstance, H, C₁₋₅alkyl, C₂₋₄haloalkyl, halo, —OC₁₋₆alkyl,—OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—NR^(a)R^(a), —NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a) or—NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a),—S(C₁₋₆alkyl), a phenyl ring substituted with 1, 2, or 3 substituentsindependently selected from R¹⁰; or R⁶ is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected fromO, N and S substituted with 0, 1, 2, or 3 substituents independentlyselected from R¹⁰; or R⁸ is independently, at each instance, H,C₁₋₅alkyl, C₂₋₄haloalkyl, halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R, —OC₂₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆ NR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a),—C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a), —S(C₁₋₆alkyl), a phenyl ringsubstituted with 1, 2, or 3 substituents independently selected fromR¹⁰, or R⁶ is a saturated or unsaturated 5- or 6-membered ringheterocycle containing 1, 2 or 3 atoms selected from O, N and Ssubstituted with 0, 1, 2, or 3 substituents independently selected fromR¹⁰.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R³ is halo, —NH₂, —NHC₁₋₃alkyl,—N(C₁₋₃alkyl)C₁₋₃alkyl or C₁₋₃alkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, Y is ═N—.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹⁰ is independently, at each instance, C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylR^(a)R^(a), —OC₂alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(IV)C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁰ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl)—S(═O)₂(C₁₋₈alkyl),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —(═O)(C₁₋₈alkyl),S═)(alkyl) —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁰ isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any one of the above andbelow embodiments, X is ═C(R²)—; and Y is ═C(R³)—.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R³ is halo, —NH₂, —NHC₁₋₃alkyl,—N(C₁₋₃alkyl)C₁₋₃alkyl or C₁₋₃alkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹⁰ is independently, at each instance, C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C 18alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)₂N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl)—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁰ is a saturatedor unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or11-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, Oand S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁰ isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl)—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(TV)S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁷ is C₁₋₅alkyl, halo or C₁₋₄haloalkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is naphthyl substituted by 0, 1, 2 or 3substituents independently selected from R⁵.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is R^(b) substituted by 0, 1, 2 or 3 substituentsindependently selected from R⁵.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is R^(b) substituted by 1, 2 or 3 substituentsindependently selected from R⁵.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹⁰ and R¹¹ together are a saturated or unsaturated3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N andS with the remaining atoms being carbon, so long as the combination of Oand S atoms is not greater than 2, wherein the each of the carbon atomsin the chain is substituted by H, ═O, C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)(C₁₋₈alkyl), —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C 18alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a), and any nitrogenatoms in the chain are substituted by H, —C₁₋₆alkylOR^(a), —C₁₋₆alkyl,—C₁₋₆alkylNR^(a)R^(a), —C₁₋₃alkylC(═O)OR^(a),—C₁₋₃alkylC(═O)NR^(a)R^(a), —C₁₋₃alkylOC(═O)C₁₋₆alkyl,—C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(c) or —C₁₋₃alkylR^(a); or

R¹¹ and R¹² together are a saturated or unsaturated 3- or 4-atom bridgecontaining 0, 1, 2 or 3 atoms selected from O, N and S with theremaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2, wherein the each of the carbon atoms in thechain is substituted by H, ═O, C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)(C₁₋₈alkyl), —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(Ia)S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a), and any nitrogenatoms in the chain are substituted by H, —C₁₋₆alkylOR^(a), —C₁₋₆alkyl,—C₁₋₆alkylNR^(a)R^(a), —C₁₋₃alkylC(═O)OR^(a),—C₁₋₃alkylC(═O)NR^(a)R^(a), —C₁₋₃alkylOC(═O)C₁₋₆alkyl,—C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(c) or —C₁₋₃alkylR^(c).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is a saturated or unsaturated 5- or 6-memberedring heterocycle containing 1, 2 or 3 atoms selected from O, N and Sthat is optionally vicinally fused with a saturated or unsaturated 3- or4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and Swith the remaining atoms being carbon, so long as the combination of Oand S atoms is not greater than 2, wherein the carbon atoms of theheterocycle and bridge are substituted by 0, 1, 2 or 3 substituentsindependently selected from C₁₋₈alkyl, C₁₋₁₄haloalkyl, halo, nitro,cyano, oxo, —OR^(a), —S(═O)_(n)C₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —OC₁₋₆alkylC(═O)OR^(a),—NR^(a)R^(a), —NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl and —NR^(a)C(═O)C₁₋₆alkyl; andunsaturated carbon atoms may be additionally substituted by ═O; and anynitrogen atoms in the chain are substituted by H, —C₁₋₆alkylOR^(a),—C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(c) or—C₁₋₃alkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is a saturated or unsaturated 5- or 6-memberedring heterocycle containing 1, 2 or 3 atoms selected from O, N and Sthat is optionally vicinally fused with a saturated or unsaturated 3- or4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and Swith the remaining atoms being carbon, so long as the combination of Oand S atoms is not greater than 2, wherein the carbon atoms of theheterocycle and bridge are substituted by 1, 2 or 3 substituentsindependently selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, nitro,cyano, oxo, —OR^(a), —S(═O)_(n)C₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —OC₁₋₆alkylC(═O)OR^(a),—NR^(a)R^(a), —NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl and —NR^(a)C(═O)C₁₋₆alkyl; andunsaturated carbon atoms may be additionally substituted by ═O; and anynitrogen atoms in the chain are substituted by H, —C₁₋₆alkylOR^(a),—C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a), —C₁₋₃alkylC(═O)OR^(a),—C₁₋₃alkylC(═O)NR^(a)R^(a), —C₁₋₃alkylOC(═O)C₁₋₆alkyl,—C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(c) or —C₁₋₃alkylR^(c).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is 10-membered bicyclic ring comprising fused6-membered rings, containing 0, 1, 2, 3 or 4 N atoms with the remainderbeing carbon atoms, with at least one of the 6-membered rings beingaromatic, wherein the carbon atoms are substituted by H, halo, OR^(a),NR^(a)R^(a), C₁₋₆alkyl and C₁₋₃haloalkyl; and unsaturated carbon atomsmay be additionally substituted by ═O.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is 10-membered bicyclic ring comprising fused6-membered rings, containing 1, 2, 3 or 4 N atoms with the remainderbeing carbon atoms, with at least one of the 6-membered rings beingaromatic, wherein the carbon atoms are substituted by H, halo, OR^(a),NR^(a)R^(a), C₁₋₆alkyl and C₁₋₃haloalkyl; and unsaturated carbon atomsmay be additionally substituted by ═O.

Another aspect of the invention relates to a method of treating acute,inflammatory and neuropathic pain, dental pain, general headache,migraine, cluster headache, mixed-vascular and non-vascular syndromes,tension headache, general inflammation, arthritis, rheumatic diseases,osteoarthritis, inflammatory bowel disorders, inflammatory eyedisorders, inflammatory or unstable bladder disorders, psoriasis, skincomplaints with inflammatory components, chronic inflammatoryconditions, inflammatory pain and associated hyperalgesia and allodynia,neuropathic pain and associated hyperalgesia and allodynia, diabeticneuropathy pain, causalgia, sympathetically maintained pain,deafferentation syndromes, asthma, epithelial tissue damage ordysfunction, herpes simplex, disturbances of visceral motility atrespiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritis, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders, comprising the step of administering a compound according toany of the above embodiments.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a compound according to any of the above embodiments and apharmaceutically-acceptable diluent or carrier.

Another aspect of the invention relates to the use of a compoundaccording to any of the above embodiments as a medicament.

Another aspect of the invention relates to the use of a compoundaccording to any of the above embodiments in the manufacture of amedicament for the treatment of acute, inflammatory and neuropathicpain, dental pain, general headache, migraine, cluster headache,mixed-vascular and non-vascular syndromes, tension headache, generalinflammation, arthritis, rheumatic diseases, osteoarthritis,inflammatory bowel disorders, inflammatory eye disorders, inflammatoryor unstable bladder disorders, psoriasis, skin complaints withinflammatory components, chronic inflammatory conditions, inflammatorypain and associated hyperalgesia and allodynia, neuropathic pain andassociated hyperalgesia and allodynia, diabetic neuropathy pain,causalgia, sympathetically maintained pain, deafferentation syndromes,asthma, epithelial tissue damage or dysfunction, herpes simplex,disturbances of visceral motility at respiratory, genitourinary,gastrointestinal or vascular regions, wounds, burns, allergic skinreactions, pruritis, vitiligo, general gastrointestinal disorders,gastric ulceration, duodenal ulcers, diarrhea, gastric lesions inducedby necrotising agents, hair growth, vasomotor or allergic rhinitis,bronchial disorders or bladder disorders.

Another aspect of the invention relates to a method of making a compoundaccording to the above embodiments, comprising the step of: reacting

with R²NH₂ to form

The compounds of this invention may have in general several asymmetriccenters and are typically depicted in the form of racemic mixtures. Thisinvention is intended to encompass racemic mixtures, partially racemicmixtures and separate enantiomers and diasteromers.

Unless otherwise specified, the following definitions apply to termsfound in the specification and claims:

“C_(α-βW)alkyl” means an alkyl group comprising a minimum of a and amaximum of β carbon atoms in a branched, cyclical or linear relationshipor any combination of the three, wherein a and 0 represent integers. Thealkyl groups described in this section may also contain one or twodouble or triple bonds. Examples of C₁₋₆alkyl include, but are notlimited to the following:

“Benzo group”, alone or in combination, means the divalent radicalC₄H₄═, one representation of which is —CH═CH—CH═CH—, that when vicinallyattached to another ring forms a benzene-like ring—for exampletetrahydronaphthylene, indole and the like.

“Halo” or “halogen” means a halogen atoms selected from F, Cl, Br and I.

“C_(V-W)haloalkyl” means an alkyl group, as described above, wherein anynumber—at least one—of the hydrogen atoms attached to the alkyl chainare replaced by F, Cl, Br or I.

“Heterocycle” means a ring comprising at least one carbon atom and atleast one other atom selected from N, O and S. Examples of heterocyclesthat may be found in the claims include, but are not limited to, thefollowing:

“Pharmaceutically-acceptable salt” means a salt prepared by conventionalmeans, and are well known by those skilled in the art. The“pharmacologically acceptable salts” include basic salts of inorganicand organic acids, including but not limited to hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, methanesuiphonic acid,ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaricacid, citric acid, lactic acid, fumaric acid, succinic acid, maleicacid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid andthe like. When compounds of the invention include an acidic functionsuch as a carboxy group, then suitable pharmaceutically acceptablecation pairs for the carboxy group are well known to those skilled inthe art and include alkaline, alkaline earth, ammonium, quaternaryammonium cations and the like. For additional examples of“pharmacologically acceptable salts,” see infra and Berge et al., J.Pharm. Sci. 66:1 (1977).

“Leaving group” generally refers to groups readily displaceable by anucleophile, such as an amine, a thiol or an alcohol nucleophile. Suchleaving groups are well known in the art. Examples of such leavinggroups include, but are not limited to, N-hydroxysuccinimide,N-hydroxybenzotriazole, halides, triflates, tosylates and the like.Preferred leaving groups are indicated herein where appropriate.

“Protecting group” generally refers to groups well known in the artwhich are used to prevent selected reactive groups, such as carboxy,amino, hydroxy, mercapto and the like, from undergoing undesiredreactions, such as nucleophilic, electrophilic, oxidation, reduction andthe like. Preferred protecting groups are indicated herein whereappropriate. Examples of amino protecting groups include, but are notlimited to, aralkyl, substituted aralkyl, cycloalkenylalkyl andsubstituted cycloalkenyl alkyl, alkyl, substituted alkyl, acyl,alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples ofaralkyl include, but are not limited to, benzyl, ortho-methylbenzyl,trityl and benzhydryl, which can be optionally substituted with halogen,alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts,such as phosphonium and ammonium salts. Examples of aryl groups includephenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl),phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl orsubstituted cycloalkylenylalkyl radicals, preferably have 6-10 carbonatoms, include, but are not limited to, cyclohexenyl methyl and thelike. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups includebenzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl,substituted benzoyl, butyryl, acetyl, tri-fluoroacetyl, tri-chloroacetyl, phthaloyl and the like. A mixture of protecting groups can beused to protect the same amino group, such as a primary amino group canbe protected by both an aralkyl group and an aralkoxycarbonyl group.Amino protecting groups can also form a heterocyclic ring with thenitrogen to which they are attached, for example,1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl andthe like and where these heterocyclic groups can further includeadjoining aryl and cycloalkyl rings. In addition, the heterocyclicgroups can be mono-, di- or tri-substituted, such as nitrophthalimidyl.Amino groups may also be protected against undesired reactions, such asoxidation, through the formation of an addition salt, such ashydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like.Many of the amino protecting groups are also suitable for protectingcarboxy, hydroxy and mercapto groups. For example, aralkyl groups. Alkylgroups are also suitable groups for protecting hydroxy and mercaptogroups, such as tert-butyl.

Silyl protecting groups are silicon atoms optionally substituted by oneor more alkyl, aryl and aralkyl groups. Suitable silyl protecting groupsinclude, but are not limited to, trimethylsilyl, triethylsilyl,tri-isopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl,1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane anddiphenylmethylsilyl. Silylation of an amino groups provide mono- ordi-silylamino groups. Silylation of aminoalcohol compounds can lead to aN,N,O-tri-silyl derivative. Removal of the silyl function from a silylether function is readily accomplished by treatment with, for example, ametal hydroxide or ammonium fluoride reagent, either as a discretereaction step or in situ during a reaction with the alcohol group.Suitable silylating agents are, for example, trimethylsilyl chloride,tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride,diphenylmethyl silyl chloride or their combination products withimidazole or DMF. Methods for silylation of amines and removal of silylprotecting groups are well known to those skilled in the art. Methods ofpreparation of these amine derivatives from corresponding amino acids,amino acid amides or amino acid esters are also well known to thoseskilled in the art of organic chemistry including amino acid/amino acidester or aminoalcohol chemistry.

Protecting groups are removed under conditions which will not affect theremaining portion of the molecule. These methods are well known in theart and include acid hydrolysis, hydrogenolysis and the like. Apreferred method involves removal of a protecting group, such as removalof a benzyloxycarbonyl group by hydrogenolysis utilizing palladium oncarbon in a suitable solvent system such as an alcohol, acetic acid, andthe like or mixtures thereof. A t-butoxycarbonyl protecting group can beremoved utilizing an inorganic or organic acid, such as HCl ortrifluoroacetic acid, in a suitable solvent system, such as dioxane ormethylene chloride. The resulting amino salt can readily be neutralizedto yield the free amine. Carboxy protecting group, such as methyl,ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can beremoved under hydrolysis and hydrogenolysis conditions well known tothose skilled in the art.

It should be noted that compounds of the invention may contain groupsthat may exist in tautomeric forms, such as cyclic and acyclic amidineand guanidine groups, heteroatom substituted heteroaryl groups (Y′=O, S,NR), and the like, which are illustrated in the following examples:

and though one form is named, described, displayed and/or claimedherein, all the tautomeric forms are intended to be inherently includedin such name, description, display and/or claim.

Prodrugs of the compounds of this invention are also contemplated bythis invention. A prodrug is an active or inactive compound that ismodified chemically through in vivo physiological action, such ashydrolysis, metabolism and the like, into a compound of this inventionfollowing administration of the prodrug to a patient. The suitabilityand techniques involved in making and using prodrugs are well known bythose skilled in the art. For a general discussion of prodrugs involvingesters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) andBundgaard Design of Prodrugs, Elsevier (1985). Examples of a maskedcarboxylate anion include a variety of esters, such as alkyl (forexample, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl(for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (forexample, pivaloyloxymethyl). Amines have been masked asarylcarbonyloxymethyl substituted derivatives which are cleaved byesterases in vivo releasing the free drug and formaldehyde (Bungaard J.Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, suchas imidazole, imide, indole and the like, have been masked withN-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)).Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloanand Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acidprodrugs, their preparation and use.

The specification and claims contain listing of species, embodiments andsub-embodiments using the language “selected from . . . and . . . ” and“is . . . or . . . ” (sometimes referred to as Markush groups). Whenthis language is used in this application, unless otherwise stated it ismeant to include the group as a whole, or any single members thereof, orany subgroups thereof. The use of this language is merely for shorthandpurposes and is not meant in any way to limit the removal of individualelements or subgroups as needed.

EXPERIMENTAL

General

Unless otherwise noted, all materials were obtained from commercialsuppliers and used without further purification. All parts are by weightand temperatures are in degrees centigrade unless otherwise indicated.All compounds showed NMR spectra consistent with their assignedstructures. Melting points were determined on a Buchi apparatus and areuncorrected. Mass spectral data was determined by electrosprayionization technique. All examples were purified to >95% purity asdetermined by high-performance liquid chromatography. Unless otherwisestated, reactions were run at room temperature. Microwave reactions wereconducted using a Smith Synthesizer® (Personal Chemistry, Inc., Upssala,Sweden) apparatus.

The following abbreviations are used:

-   aq—aqueous-   BINAP—2,2′-bis(diphenylphosphino)-1,1′-binaphthyl-   brine—saturated aqueous NaCl-   concd—concentrated-   DMF—N,N-dimethylformamide-   Et₂O—diethyl ether-   BSA—N,O-bis(trimethylsilyl)acetamide-   BSTFA—N,O-bis(trimethylsilyl)trifluoroacetamide-   NMP N-methylpyrrolidinone-   EtOAc—ethyl acetate-   EtOH—ethyl alcohol-   h—hour-   min—minutes-   MeOH—methyl alcohol-   satd—saturated-   THF—tetrahydroftiran-   TLC— thin layer chromatography

Example 1

(a) 4-(4-tert-Butylphenyl)-6-chloropyrimidin-2-ylamine. To a 250-mL,round-bottomed flask containing 2-amino-4,6-dichloropyrimidine (0.88 g,5.4 mmol, Lancaster) in CH₃CN (35 mL), was added4-tert-butylphenylboronic acid (0.80 g, 4.5 mmol, Aldrich) and Pd(PPh₃)₄(0.26 g, 0.23 mmol, Aldrich). A solution of 10% Na₂CO₃ (20 mL) was addedand the resulting mixture was stirred at 90° C. for 10 h under a N₂atmosphere. The reaction mixture was allowed to cool to roomtemperature. The organic phase was collected and dried over Na₂SO₄. Thesolution was filtered and the concentrated in vacuo to afford the crudeproduct, and column chromatography over silica gel with hexane: EtOAc(3:1) gave the desired product as a clear oil. MS (ESI, pos. ion) m/z:262 (M+1).

(b) N⁴-Benzothiazol-6-yl-6-(4-tert-butylphenyl)pyrimidine-2,4-diaminehydrochloride. To a 25-mL, round-bottomed flask containing4-(4-tert-butylphenyl)-6-chloropyrimidin-2-ylamine (0.16 g, 0.59 mmol),was added 6-amino-benzothiazole (0.11 g, 0.71 mmol, Lancaster) and EtOH(8 mL). The solution was heated at reflux for 20 h under a N₂atmosphere. The mixture was concentrated in vacuo and the residue wastaken in a solvent mixture (20 mL, 1:1 of MeOH:CH₂Cl₂). The solution wasfiltered and the concentrated in vacuo to afford the product (50 mg,23%) as a white solid. The formation of hydrochloride salt was achievedby re-dissolving the product solid (50 mg, 0.13 mmol) in a solventmixture (8 mL, 1:1 v/v, MeOH:CH₂Cl₂), adding a solution of HCl (0.14 mL,0.14 mmol, 1.0 N in Et₂O, Aldrich), and concentrating the solution invacuo. The title compound was obtained as an off-white solid. MP:220-222° C. MS (ESI, pos. ion.) m/z: 376 (M+1).

Example 2

(a) 6-(4-tert-Butylphenyl)-2-methylpyrimidin-4-ol. To a 250-mL,round-bottomed flask was added ethyl 3-(4-tert-butylphenyl)prop-2-ynoate(1.5 g, 6.5 mmol), EtOH (50 mL), acetamidine hydrochloride (1.5 g, 16mmol, Aldrich) and sodium ethoxide (1.6 g, 23 mmol, Aldrich). Theresulting solution was heated at reflux under N₂ for 16 h. The reactionmixture was allowed to cool to 25° C., the solvent was removed in vacuo,and the residue was treated with EtOAc (100 mL) and water (25 mL). Themixture was acidified to pH˜4.0 with 2 N HCl. The organic phase wasseparated and washed with water (20 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. Purification by silica gel chromatography (stepgradient, 1:1 hexane/EtOAc, then 20:20:1 hexane/EtOAc/MeOH) provided thetitle product as a white solid. MS (ESI, pos. ion) m/z: 243 (M+1).

(b) 6-(4-tert-Butylphenyl)-4-chloro-2-methylpyrimidine. To a 100-mL,round-bottomed flask was added6-(4-tert-butylphenyl)-2-methylpyrimidin-4-ol (0.15 g, 0.62 mmol) andphosphorus oxychloride (8.0 mL, 86 mmol, Aldrich). The resultingsolution was heated at reflux under N₂ for 3 h. The solution wasconcentrated in vacuo to provide the title product as a yellow oil. MS(ESI, pos. ion) m/z: 261 (M+1).

(c)[6-(4-tert-Butylphenyl)-2-methylpyrimidin-4-yl]-(2,3-dihydrobenzo[1,4]-dioxin-6-yl)amine.To a 100-mL, round-bottomed flask containing6-(4-(tert-butylphenyl)-4-chloro-2-methylpyrimidine (0.14 g, 0.60 mmol)in 1,4-dioxane (8 mL) was added 1,4-benzodioxane-6-amine (0.11 g, 0.72mmol, Aldrich). The reaction mixture was heated at reflux under N₂ for 5h. The solvent was removed in vacuo and the crude product was purifiedby silica gel chromatography (3:1 hexane/EtOAc) to afford the titleproduct as a yellow oil. MS (ESI, pos. ion) m/z: 376 (M+1).

Example 3

(a) 6-(4-tert-Butylphenyl)-2,4-dichloropyrimidine. (Analogous to theprocedures of Finch, H. J. Chem. Soc., Perkin Trans. 1 1994, 9, 1193;Gong, Y. Synlett 2000, 6, 829). To a 250-mL, round-bottomed flaskcontaining 2,4,6-trichloropyrimidine (26 g, 0.14 mol, Aldrich) in CH₃CN(100 mL) was added 4-tert-butylphenylboronic acid (7.2 g, 40 mmol,Aldrich) and Pd(PPh₃)₄ (1.4 g, 1.2 mmol, Aldrich). The mixture wastreated with 10% aq Na₂CO₃ (60 mL) then magnetically stirred under N₂ at90° C. overnight. The reaction mixture was diluted with EtOAc (80 mL),CH₃CN (50 mL) and water (50 mL). The mixture was allowed to cool to 25°C. and the resulting precipitate was collected by filtration. Theprecipitate was dissolved in CH₂Cl₂ (140 mL), washed with satd NaCl (60mL), dried over Na₂SO₄, filtered and concentrated in vacuo. Purificationby silica gel chromatography (6:1 hexane/EtOAc) provided the titleproduct. MS (ESI, pos. ion) m/z: 281 (M+1).

(b)[6-(4-tert-Butylphenyl)-2-chloropyrimidin-4-yl]-(2,3-dihydrobenzo[1,4]-dioxin-6-yl)amine.(Analogous to the procedure of Abdel-Fattah, A. J. Chem. Res. Synop.1994, 11, 412). To a 250-mL, round-bottomed flask containing6-(4-tert-butylphenyl)-2,4-dichloropyrimidine (3.0 g, 11 mmol) in 1:1EtOH/1,4-dioxane (100 mL) was added 1,4-benzodioxane-6-amine (1.3 g, 8.6mmol, Aldrich). The reaction mixture was stirred at 25° C. overnight andthe solvent was removed in vacuo. Purification by silica gelchromatography (6:1 hexane/EtOAc) provided the title product as anoff-white solid. MS (ESI, pos. ion) m/z: 396 (M+1).

Example 4

(a) 6-(4-tert-Butylphenyl)-4-chloropyrimidine-2-ylamine. To a 100-mL,round-bottomed flask containing 4,6-dichloro-2-aminopyrimidine (0.87 g,5.4 mmol, Aldrich) in 35 mL CH₃CN were added 4-tert-butylphenylboronicacid (0.80 g, 4.5 mmol, Aldrich) and Pd(PPh₃)₄ (0.26 g, 0.23 mmol,Aldrich). 10% aq Na₂CO₃ (20 mL) was added and the mixture was stirredunder N₂ at 90° C. overnight. The organic phase was collected and driedover Na₂SO₄. Purification by silica gel chromatography with hexane/EtOAc(3:1) gave the desired product as a clear oil. MS (ESI, pos. ion) m/z:262 (M+1).

(b)[2-Amino-6-(4-tert-butylphenyl)pyrimidin-4-yl]-(2,3-dihydrobenzo[1,4]-dioxin-6-yl)aminehydrochloride. To a 250-mL, round-bottomed flask containing6-(4-tert-butylphenyl)-4-chloropyrimidin-2-ylamine (0.16 g, 0.59 mmol)in EtOH (8 mL), was added 1,4-benzodioxane-6-amine (0.11 g, 0.71 mmol,Aldrich). The solution was refluxed for 8 h and the solvent was removedin vacuo. Purification of the residue by silica gel chromatography(10:10:1 hexane/EtOAc/MeOH) afforded the title compound as a free base(0.13 g, 57%). The hydrochloride salt was prepared by dissolving thefree base (0.13 g, 0.35 mmol) in MeOH (8 mL). To the solution was addedHCl (0.35 mL, 0.35 mmol, 1.0 M HCl in Et₂O, Aldrich), the mixture wasstirred at 25° C. for 10 min, and the solvent was removed in vacuo toprovide the title product. MP: 221-224° C. MS (ESI, pos. ion) m/z: 377(M+1).

Example 5

(a) 4-Chloro-6-(4-trifluoromethylphenyl)pyrimidine

To a 500-mL, round-bottomed flask was added 4,6-dichloropyrimidine (14g, 95 mmol, Aldrich), 4-(trifluoromethyl)phenylboronic acid (6.0 g, 32mmol, Aldrich), acetonitrile (95 mL) and 1 M aq sodium carbonate (95mL). The mixture was deoxygenated by sparging with N₂ for 15 min. Thecatalyst, Pd(PPh₃)₄ (1.9 g, 1.6 mmol, Strem), was added and the yellowmixture was heated at 80° C. for 15 h. After cooling to 25° C., thesolution was concentrated to remove the acetonitrile. The solution wasdiluted with aq NaHCO₃ and extracted with CH₂Cl₂. The combined extractswere dried over Na₂SO₄, filtered and concentrated in vacuo. Purificationby silica gel chromatography with gradient from 1.5% to 10% solution ofethyl acetate in hexane afforded the title compound as a white solid. MS(ESI, pos. ion) m/z: 259 (M+1).

(b)(1H-Benzotriazol-5-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine.A mixture of 4-chloro-6-(4-trifluoromethylphenyl)pyrimidine (0.10 g,0.39 mmol), 5-aminobenzotriazole (0.052 g, 0.39 mmol, Lancaster) andethanol (1 mL) was heated in a microwave at 180° C. for 20 min. Themixture was diluted with satd NaHCO₃ and extracted with EtOAc. Thecombined extracts were dried over Na₂SO₄, filtered and concentrated invacuo. Purification by silica gel chromatography with gradient from 30%to 70% solution of ethyl acetate in hexane afforded the product as ayellow solid. MS (ESI, pos. ion) m/z: 357 (M+1).

Example 6

(a) 7-Nitro-1,2,3,4-tetrahydroquinoline. 1,2,3,4-Tetrahydroquinoline (19mL, 0.15 mol, Aldrich) was added dropwise into concd H₂SO₄ (54 mL) withstirring over 30 min at 0° C. To the solution was then added dropwisewith stirring a mixture of concd H₂SO₄ (30 mL) and 90% HNO₃ (6.4 mL,0.17 mol) for about 2.5 h while the internal reaction temperature wasmaintained at 5-10° C. by cooling with an ice bath. The reaction mixturewas stirred for 2.5 h and allowed to warm slowly to 25° C. The mixturewas then added to crushed ice (−1 L) and treated with solid KOH, withstirring, until pH 8 was reached. The resulting suspension was filteredand the filtrate was washed with EtOAc (1.5 L). The aqueous phase wasextracted with EtOAc (2×500 mL), the EtOAc phases were combined, washedwith 1 N NaOH (1 L) and satd NaCl (500 mL), dried over MgSO₄, filteredand concentrated in vacuo. Purification by silica gel chromatography(8:1 hexane/EtOAc) afforded the title compound as bright-orangecrystals. MS (ESI, pos. ion) m/z 179 (M+1).

(b) 7-Nitroquinoline. A solution of 7-nitro-1,2,3,4-tetrahydroquinoline(4.0 g, 22 mmol) in dichloromethane (500 mL) was stirred at 25° C. andtreated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (10 g, 44 mmol,Aldrich) in portions. The reaction mixture was stirred at 25° C. for 1h, then filtered and the filtercake was washed with dichloromethane. Thefiltrate was concentrated to give a brown solid (4.4 g). The crudeproduct was dissolved in hot EtOAc (200 mL), treated with decolorizingcarbon (1 g), filtered though Celiteo, and concentrated.Recrystallization from EtOAc provided the title product as an orange-tansolid. Purification of the concentrated mother liquors by silica gelchromatography (25% EtOAc/hexane) provided an additional amount of thetitle product as an off-white solid.

(c) 7-Quinolylamine. A solution of 7-nitroquinoline (3.2 g, 18 mmol) inMeOH (200 mL) was purged with N₂ and treated with 10% palladium oncarbon (1.0 g, Aldrich). The suspension was purged with H₂ andmagnetically stirred under 1 atmosphere H₂ for 16 h. The mixture waspurged with N₂, filtered though Celite® and concentrated in vacuo.Purification by silica gel chromatography with gradient from 5% to 10%solution of MeOH in dichloromethane provided the title product as abrown solid. MS (ESI, pos. ion) m/z 145 (M+1).

(d) Quinolyl-7-yl-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine. To aglass vial with a magnetic stir bar was added4-chloro-6-(4-trifluoromethyl-phenyl)pyrimidine, Example 5(a), (0.30 g,1.2 mmol,) and 7-quinolylamine (0.17 g, 1.2 mmol). The solids werestirred and heated in a microwave at 200° C. for 10 min. The resultingsolid was partitioned between satd NaHCO₃ (100 mL) and EtOAc (200 mL).The organic phase was washed with satd NaCl (50 mL), dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product was purified bysilica gel chromatography (60% ethyl acetate/hexane), purified again bysilica gel chromatography (50% EtOAc/dichloromethane) and concentratedto a solid, which was triturated with 1:1 CH₂Cl₂/hexane (50 mL). Thesolid was dried in vacuo at 60° C. overnight to afford the title productas a pale-tan solid. MP: 260° C. MS (ESI, pos. ion) m/z: 367 (M+1).

Example 7

4-Methyl-7-{[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amino}quinolin-2-ol, hydrochloride. Analogous to the procedure used to prepareExample 5(b), 4-chloro-6-(4-trifluoromethylphenyl)pyrimidine, Example5(a), (150 mg, 0.58 mmol) and carbostyril 124 (50 mg, 0.29 mmol,Aldrich) afforded, after recrystallization from MeOH, the title productas bright-yellow crystals. MP: 373° C. (with decomposition). MS (ESI,pos. ion) m/z: 397 (M+1).

Example 8

(a) Ethyl 3-(4-tert-butylphenyl)prop-2-ynoate. To a 500-mL,round-bottomed flask containing a solution of4-tert-butylphenylacetylene (10 g, 64 mmol, GFS Chemicals) in THF (150mL) was added n-butyllithium (40 mL, 64 mmol, 1.6 M in hexane, Aldrich)with stirring at −78° C. After the addition was complete, the reactionmixture was stirred at −78° C. for 40 min. The solution was then allowedto warm to 0° C. and stirred for 30 min. The solution was cooled to −78°C. and treated with ethyl chloroformate (6.1 mL, 64 mmol, Aldrich).After stirring for 2 h, the solution was allowed to warm to 25° C. andstirred overnight. The reaction was quenched with 5% aq NaHCO₃ (80 mL)and satd NaCl (80 mL) and extracted with EtOAc (2×130 mL). The combinedextracts were washed with water (2×15 mL), dried over Na₂SO₄, filteredand concentrated in vacuo. Purification by silica gel chromatography(20:1 hexane/EtOAc) provided the title product. MS (ESI, pos. ion) m/z:231 (M+1).

(b) 6-[4-tert-Butylphenyl)pyrimidin-4-ol. (Analogous to the procedure ofHaddach, M. J. Fluorine Chem. 1991, 51, 197). To a 250-mL,round-bottomed flask was added ethyl 3-(4-tert-butylphenyl)prop-2-ynoate(1.9 g, 8.4 mmol), EtOH (100 mL), formamidine hydrochloride (10 g, 0.13mol, Aldrich) and diisopropylethylamine (22 mL, 0.13 mol, Aldrich). Thesolution was heated at reflux under N₂ for 6 h. The reaction mixture wasallowed to cool to 25° C., the solvent was removed in vacuo, and theresidue was heated at 170° C. under N₂ for 2 h. The residue was allowedto cool to 25° C. and dissolved in EtOH (15 mL). The solution wastreated with sodium ethoxide (15 mL, 21 wt %, 46 mmol, Aldrich), thenheated at reflux under N₂ for 4 h. The reaction mixture was diluted withEtOAc (100 mL) and acidified to pH 4.0 with 2 N HCl. The organic phasewas separated and washed with water (50 mL), dried over Na₂SO₄, filteredand concentrated in vacuo. Purification by silica gel chromatography(step gradient, 1:1 hexane/EtOAc then 20:20:1 hexane/EtOAc/MeOH)provided the title product as an off-white solid. MS (ESI, pos. ion)m/z: 229 (M+1).

(c) 6-(4-tert-Butylphenyl)-4-chloropyrimidine. To a 100-mL,round-bottomed flask was added 6-(4-tert-butylphenyl)pyrimidin-4-ol(0.73 g, 3.2 mmol) and phosphorus oxychloride (25 mL, 0.27 mol,Aldrich). The resulting solution was heated at reflux under N₂ for 3 h.The solution was concentrated in vacuo to provide the title product as ayellow oil. MS (ESI, pos. ion) m/z: 247 (M+1).

(d)[6-(4-tert-Butylphenyl)pyrimidin-4-yl]-(2,3-dihydrobenzo[1,4]dioxin-6-yl)amine.To a 100-mL, round-bottomed flask containing6-(4-tert-butylphenyl)-4-chloropyrimidine (0.25 g, 1.0 mmol) in1,4-dioxane (5 mL), was added 1,4-benzodioxane-6-amine (0.15 g, 1.0mmol, Aldrich). The solution was heated at reflux under N₂ for 3 h. Thesolvent was removed in vacuo and the residue was purified by silica gelchromatography (2:1 hexane/EtOAc) to provide the title product as anoff-white solid. MS (ESI, pos. ion) m/z: 362 (M+1). MP: 199-202° C.

Example 9

(a) Ethyl 3-(2,4-dinitrophenyl)prop-2-enoate. A mixture of2,4-dinitrobenz-aldehyde (10 g, 51 mmol, Avocado) and methyl(triphenylphosphoranylidene)-acetate (17 g, 51 mmol, Aldrich) in benzene(200 mL) was heated at reflux with stirring under N₂ for 3 h. Thereaction mixture was allowed to cool to 25° C. and diluted with Et₂O(500 mL). The mixture was washed with water (3×200 mL) and satd NaCl(100 mL), dried over MgSO₄, filtered and concentrated in vacuo.Purification by silica gel chromatography (4:1 hexane/EtOAc) providedthe title product as a bright-yellow solid.

(b) 7-Amino-3,4-dihydro-1H-quinolin-2-one. To a solution of ethyl3-(2,4-dinitrophenyl)prop-2-enoate (10 g, 38 mmol) in EtOH (150 mL) andglacial acetic acid (10 mL) was added 10% palladium on carbon (5.0 g,Aldrich), and the mixture was hydrogenated on a Parr shaker apparatus at25° C., under 60 psi H₂, for 6 h. The reaction mixture was purged withN₂, filtered though Celite® and the filtercake was washed with EtOH (400mL). The filtrate was concentrated in vacuo to provide the title productas a yellow solid. MS (ESI, pos. ion) m/z: 163 (M+1).

(c)3,4-Dihydro-7-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]-1H-quinolin-2-one.A mixture of 4-chloro-6-(4-trifluoromethylphenyl)pyrimidine, Example5(a), (3.2 g, 12 mmol) and 7-amino-1,3,4-trihydroquinolin-2-one (1.0 g,6.2 mmol) in EtOH (20 mL) was stirred at reflux for 4.5 h. The resultingsuspension was allowed to cool to 25° C., then diluted with EtOAc (100mL). The solid was collected by filtration, washed with EtOAc (30 mL)and hexane (30 mL), and dried in vacuo to afford 2.9 g (97%)7-[6-(4-(trifluoromethylphenyl)-pyrimidin-4-ylamino]-3,4-dihydro-1H-quinolin-2-onehydrochloride as a bright-yellow solid. A portion of the solid (460 mg,1.1 mmol) was partitioned between EtOAc (200 mL) and 1 N NaOH (100 mL).The organic phase was separated and washed with water (50 mL) and satdNaCl (50 mL), then dried in vacuo onto silica gel. Purification bysilica gel chromatography (5% MeOH/dichloro-methane) provided 380 mg(90%) of the title product as an amorphous off-white solid. MS (ESI,pos. ion) m/z: 385 (M+1).

Example 10

(a) 7-Aminoquinolin-2-ol. 7-Amino-3,4-dihydro-1H-quinolin-2-one, Example9(b), (1.0 g, 6.2 mmol) was suspended in anhydrous 1,4-dioxane (20 mL),under N₂, in a flame-dried, round-bottomed flask equipped with a refluxcondenser. The suspension was magnetically stirred at 25° C. and treatedwith 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.7 g, 7.5 mmol,Aldrich) followed by N,O-bis(trimethylsilyl)acetamide (7.6 mL, 3.1 mmol,Aldrich). The reaction mixture was stirred in a 105° C. oil bath for 45min, then filtered while hot through a fine sintered-glass funnel. Thefiltrate was concentrated in vacuo, then filtered though a short plug ofsilica gel (5% MeOH in dichloromethane) and concentrated again toprovide 3.1 g of a brown solid. The solid was dissolved in 1 N HCl andwashed with EtOAc. The pH of the aqueous phase was adjusted to −5 by theaddition of 5 N NaOH and glacial acetic acid. The solution was saturatedwith NaCl and extracted with n-butanol until the aqueous phase appearedto be free of product by TLC. The combined n-butanol extracts wereconcentrated in vacuo. Purification of the residue by silica gelchromatography (5% MeOH in dichloromethane) provided 180 mg (18%) of thetitle product as a pale orange solid. MS (ESI, pos. ion) m/z: 161 (M+1).

(b) 7-[6-(4-Trifluoromethylphenyl)pyrimidin-4-ylamino]quinolin-2-ol. Amixture of 4-chloro-6-(4-trifluoromethylphenyl)pyrimidine, Example 5(a),(0.48 g, 1.9 mmol), 7-aminoquinolin-2-ol (0.15 g, 0.94 mmol) and EtOH(1.5 mL) was stirred and heated in a microwave at 160° C. for 10 min.The resulting bright-yellow solid was collected by filtration and washedwith EtOAc (30 mL) and hexane (30 mL). The solid was suspended in 1 NNaOH (100 mL), shaken vigorously, then the suspension was acidified topH˜5 with glacial AcOH at 0° C. The resulting suspension was filteredand the solid purified by silica gel chromatography (step gradient:5-10% MeOH in dichloromethane), recrystallized from MeOH anddichloromethane, and dried in vacuo at 80° C. to provide 255 mg (71%) ofthe title product as pale yellow crystals. MS (ESI, pos. ion) m/z: 383(M+1). MP: 337° C. (with decomposition).

Example 11

(2-Chloroquinolin-7-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine.7-[6-(4-(Trifluoromethylphenyl)pyrimidin-4-ylamino]-3,4-dihydro-1H-quinolin-2-onehydrochloride, Example 9(c), (500 mg, 1.2 mmol) was suspended inanhydrous 1,4-dioxane (10 mL), under N₂, in a flame-dried,round-bottomed flask equipped with a reflux condenser. The suspensionwas magnetically stirred at ° C. and treated with2,3-dichloro-5,6-dicyano-1,4-benzoquinone (350 mg, 1.5 mmol, Aldrich)followed by bis(trimethylsilyl)trifluoroacetamide (1.4 mL, 5.3 mmol,Aldrich). The reaction mixture was stirred in a 105° C. oil bath for 15min, then allowed to cool to 25° C. and partitioned between EtOAc (150mL) and 1% aq NaHSO₃ (100 mL). The resulting emulsion was allowed tosettle, and the organic phase was separated and concentrated in vacuo toa brown solid (1.1 g). The solid was treated with phosphorousoxychloride (10 mL, Aldrich) and stirred in a 100° C. oil bath for 1 h.After cooling to room temp, the reaction was quenched by slow additionto MeOH (200 mL), then concentrated in vacuo. The residue was treatedwith a mixture of 30% NHOH and ice (200 mL), then extracted with EtOAc(2×100 mL). The combined organic extract was washed with satd NaCl (50mL), dried over Na₂SO₄, filtered and concentrated in vacuo. Purificationby silica gel chromatography (30% EtOAc in hexane) provided a mixture ofthe title product and(2-methoxyquinolin-7-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine(Example 12), and the pure title product as a white solid. MS (ESI, pos.ion) m/z: 401 (M+1). MP: 233° C.

Example 12

(2-Methoxyquinolin-7-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine.A mixture of(2-chloroquinolin-7-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amineand(2-methoxyquinolin-7-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine,Example 11, (210 mg) was dissolved in a solution of HCl in MeOH,prepared by the addition of acetyl chloride (5 mL) to MeOH (50 mL). Thereaction mixture was stirred at 25° C. for 15 h, and heated at refluxfor 2 h. The solution was concentrated in vacuo and the residuepartitioned between EtOAc (50 mL) and 1 N NaOH (50 mL). The organicphase was washed with water (20 mL), satd NaCl (20 mL), dried overNa₂SO₄, filtered and concentrated in vacuo. Purification by silica gelchromatography (25% EtOAc in hexane) followed by recrystallization fromEtOAc and hexane, provided the title product as white crystals. MS (ESI,pos. ion) m/z: 397 (M+1). MP: 199° C.

Example 13

(a) 7-[6-(4-Trifluoromethylphenyl)pyrimidin-4-ylamino]quinolin-2-olhydrochloride.7-[6-(4-(Trifluoromethylphenyl)pyrimidin-4-ylamino]-3,4-dihydro-1H-quinolin-2-onehydrochloride, Example 9(c), (1.0 g, 2.4 mmol) was suspended inanhydrous 1,4-dioxane (15 mL), under N₂, in a flame-dried,round-bottomed flask equipped with a reflux condenser. The suspensionwas magnetically stirred at 25° C. and treated with2,3-dichloro-5,6-dicyano-1,4-benzoquinone (710 mg, 3.1 mmol, Aldrich)followed by bis(trimethylsilyl)-trifluoroacetamide (2.8 mL, 10.5 mmol,Aldrich). The reaction mixture was stirred in a 105° C. oil bath for 75min, then allowed to cool to 25° C. and concentrated to a volume of 5mL. The mixture was treated with 1 N HCl (100 mL) and EtOAc (100 mL) andshaken vigorously. The resulting fine precipitate was collected byfiltration and air-dried to afford the title product as a green-tansolid. MS (ESI, pos. ion) m/z: 383 (M+1).

(b)(2-Chloroquinolin-7-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine.A mixture of7-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]quinolin-2-olhydrochloride (810 mg, 1.9 mmol) and phosphorous oxychloride (5 mL) wasmagnetically stirred in a 100° C. oil bath for 1 h. The reaction mixturewas allowed to cool to 25° C., then added slowly to 30% NH₄OH (100 mL)diluted up to 150 mL with crushed ice. The mixture was concentrated invacuo to −100 mL and the resulting dark brown precipitate was collectedby filtration. The aqueous phase was extracted with n-butanol (100 mL),and the extract and the precipitate were combined and concentrated invacuo. Purification by silica gel chromatography with gradient from 10%to 30% solution of EtOAc in dichloromethane provided the title product.MS (ESI, pos. ion) m/z: 401 (M+1).

(c)(2-Azidoquinolin-7-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine.A solution of(2-chloroquinolin-7-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine(500 mg, 1.2 mmol) in dimethyl sulfoxide (8 mL) was treated with sodiumazide (810 mg, 12 mmol) and magnetically stirred in a 110° C. oil bathfor 18 h. The reaction mixture was allowed to cool to 25° C. and treatedwith water (100 mL) and EtOAc (100 mL). The mixture was vigorouslyshaken and the resulting precipitate collected by filtration to providethe title product. MS (ESI, pos. ion) m/z: 408 (M+1).

(d) N⁷-[6-(4-Trifluoromethylphenyl)pyrimidin-4-yl]quinoline-2,7-diamine.A mixture of(2-azidoquinolin-7-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine(425 mg, 1.0 mmol) and triphenylphosphine (330 mg, 1.3 mmol, Aldrich) in1,4-dioxane (30 mL) was treated with water (15 mL) and concd HCl (0.5mL). The reaction mixture was stirred at reflux for 3 h thenconcentrated in vacuo to −15 mL. The mixture was treated with satdNaHCO₃ (100 mL) and extracted with EtOAc (100 mL). The organic phase waswashed with water (50 mL), satd NaCl (50 mL), dried over Na₂SO₄,filtered and concentrated onto silica gel. Purification by silica gelchromatography with 5% solution of MeOH in dichloromethane followed by5% solution of (1 M NH₃ in MeOH) in dichloromethane provided the titleproduct as a pale-yellow amorphous solid. MS (ESI, pos. ion) m/z: 382(M+1).

Example 14

(a) (3-Trifluoromethylphenyl)carbamic acid tert-butyl ester. To a250-mL, round-bottomed flask was added 3-(trifluoromethyl)aniline (5.0g, 31 mmol, Aldrich), THF (100 mL), di-tert-butyl dicarbonate (20.0. g,93 mmol, Aldrich) and 4-(dimethylamino)pyridine (0.38 g, 3.1 mmol,Aldrich). The mixture was heated at reflux for 3 h. K₂CO₃ (13 g, 93mmol) and MeOH (50 mL) were added, and heating was continued overnight.After cooling to room temperature, the mixture was diluted with CH₂Cl₂,then filtered and washed with CH₂Cl₂ and the filtrate was concentratedto afford a brown oil. The oil was dissolved in EtOAc (200 mL) andwashed with H₂O (2×100 mL), brine (1×100 mL), dried over Na₂SO₄ andconcentrated in vacuo onto silica gel. Purification by silica gelchromatography with gradient from 0% to 15% solution of EtOAc in hexaneafforded the title compound as a colorless oil which solidified uponstanding to a while solid. MS (ESI, neg. ion.) m/z: 260 (M−1).

(b) [2-(6-Chloropyrimidin-4-yl)-5-trifluoromethylphenyl]carbamic acidtert-butyl ester. (Analogous to the procedures of Boisnard, S.;Carbonnelle, A. C.; Zhu, J. Org Let. 2001, 3, 2061-2064 and Hewawasam,P.; Meanwell, N. A. Tetrahedron Lett. 1994, 35, 7303). To a 500-mL,round-bottomed flask containing (3-trifluoromethylphenyl)carbamic acidtert-butyl ester (2.5 g, 9.6 mmol) in THF (100 mL) stirred at −40° C.was added sec-BuLi (17 mL, 1.3 M in cyclohexane, Aldrich) over 10 min.The mixture was stirred for 1 h at 40° C. and then cooled to −78° C.Trimethyl borate (4.4 mL, 38 mmol, Aldrich) was added over 10 min. Thereaction mixture was allowed to warm to room temperature and stirred for10 min at that temperature. The mixture was quenched with aq KH₂PO₄ andconcentrated to remove the THF. The aqueous mixture was then extractedwith EtOAc (3×100 mL) and the combined extracts were washed with brine,dried over Na₂SO₄, and concentrated to afford a yellow foam. The foamwas dissolved in CH₃CN (30 mL) and treated with 4,6-dichloropyrimidine(4.1 g, 28 mmol, Aldrich) followed by a solution of Na₂CO₃ (2.9 g, 28mmol) in H₂O (30 mL). Tetrakis(triphenylphosphine)palladium(0) (0.53 g,0.46 mmol, Strem) was then added and the mixture was stirred at 75° C.for 15 h. After allowing to cool to room temperature, the mixture wasconcentrated in vacuo to remove the CH₃CN and then extracted with EtOAc.The combined extracts were washed with H₂O and brine, dried over Na₂SO₄and concentrated in vacuo. Purification of the residue by silica gelchromatography with gradient from 0% to 10% solution of EtOAc in hexaneafforded the title compound as a colorless oil. MS (ESI, pos. ion.) m/z:374 (M+1).

(c)[6-(2-Amino-4-trifluoromethylphenyl)pyrimidin-4-yl]benzothiazol-6-ylamine.Analogous to the procedure used to prepare Example 5(b),[2-(6-chloropyrimidin-4-yl)-5-trifluoromethylphenyl]carbamic acidtert-butyl ester (1.0 g, 2.7 mmol), and 6-aminobenzothiazole (0.80 g,5.35 mmol, Lancaster) afforded after purification by silica gelchromatography with gradient from 0.5 to 3.0% solution of (2 M NH₃ inMeOH) in CH₂Cl₂ a crude material, which was subjected to a secondpurification by silica gel chromatography with gradient from 1.3% to1.4% solution of (2 M NH₃ in MeOH) in CH₂Cl₂ to give the title compoundas a yellow solid. MS (ESI, pos. ion) m/z: 388 (M+1). MP: 203.1-203.2°C.

Example 15

Benzothiazol-6-yl-[6-(2-cyclohexylmethylamino-4-trifluoromethylphenyl)-pyrimidin-4-yl]amine.To a 5-mL, round-bottomed flask was added[6-(2-amino-4-trifluoromethylphenyl)pyrimidin-4-yl]benzothiazol-6-ylamine(0.060 g, 0.15 mmol), 1,2-dichloroethane (1 mL), acetic acid (0.018 mL,0.31 mmol) and cyclohexanecarboxaldehyde (0.055 mL, 0.45 mmol, Aldrich).Sodium triacetoxy-borohydride (0.083 g, 0.39 mmol, Aldrich) was added tothe mixture with stirring at 0° C. and the mixture was stirring for 17 hat room temperature. The reaction mixture was diluted with EtOAc (3 mL)and quenched with H₂O (3 mL) and satd NaHCO₃ (7 mL). The phases wereseparated and the aqueous phase was extracted with EtOAc (3×3 mL). Thecombined organic extracts were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo onto silica gel. Purification by silica gelchromatography with gradient from 20% to 50% solution of EtOAc in hexaneafforded the title compound as a yellow solid. MS (ESI, pos. ion.) m/z:484 (M+1).

Example 16

(a) N-(4-Nitrobenzothiazol-2-yl)acetamide. 4-Nitrobenzothiazol-2-ylamine(860 mg, 4.4 mmol, Helv. Chim. Acta 1940 23, 328) and acetic anhydride(10 mL, 105 mmol) were heated to 80° C. for 2 h. The reaction was cooledto room temperature and diluted with Et₂O. The solid was filtered andstirred vigorously with Et₂O. The solid was filtered again, washed withEt₂O and dried in vacuo to give the title product as a light yellowamorphous solid. MS (ESI, pos. ion.) m/z: 238 (M+1).

(b) N-(4-Aminobenzothiazol-2-yl)acetamide. A mixture ofN-(4-nitrobenzo-thiazol-2-yl)acetamide (840 mg, 3.5 mmol), NH₄Cl (196mg, 3.7 mmol, Aldrich) and iron dust (996 mg, 18 mmol, Aldrich) in 70%aqueous MeOH (25 mL) was heated to 65° C. After 1 h the reaction mixturewas filtered while hot and the filtrate was concentrated in vacuo. Theresidue was purified by silica gel column chromatography with gradientfrom 0% to 3.5% solution of (2 M NH₃ in MeOH) in CH₂Cl₂ to give thetitle product as a white amorphous solid. MS (ESI, pos. ion.) m/z: 208(M+1).

(c)N-{4-[6-(4-Trifluoromethylphenyl)pyrimidin-4-ylamino]benzothiazol-2-yl}acetamide.To a glass tube was added4-chloro-6-(4-trifluoromethylphenyl)-pyrimidine, Example 5(a), (280 mg,1.1 mmol), N-(4-aminobenzothiazol-2-yl)acetamide (197 mg, 0.95 mmol),CuI (55 mg, 0.30 mmol, Aldrich) and EtOH (2.5 mL). The reaction mixturewas heated in a microwave at 160° C. for 15 min. The solution wasdecanted and purified twice by silica gel column chromatography withgradient from 0% to 4% solution of (2 M NH₃ in MeOH) in CH₂Cl₂ to givethe title product as a yellow amorphous solid. MS (ESI, pos. ion.) m/z:430 (M+1). MP:>250° C.

Example 17

(a) Benzothiazole-2,4-diamine. This compound was prepared according toExample 16(b) using 4-nitrobenzothiazol-2-ylamine (640 mg, 3.3 mmol,Helv. Chim. Acta 1940 23, 328), NH₄Cl (180 mg, 3.3 mmol) and iron dust(785 mg, 14 mmol) in 75% aq MeOH (25 mL). The reaction was purified byflash column chromatography on silica gel with gradient from 0% to 5%solution of (2 M NH₃ in MeOH) in CH₂Cl₂ to give the title product as alight yellow amorphous solid. MS (ESI, pos. ion.) m/z: 166 (M+1).

(b)N⁴-[6-(4-Trifluoromethylphenyl)pyrimidin-4-yl]benzothiazole-2,4-diamine.This compound was prepared according to Example 16(c) using4-chloro-6-(4-trifluoromethylphenyl)pyrimidine, Example 5(a), (495 mg,1.9 mmol), benzothiazole-2,4-diamine (320 mg, 1.9 mmol) and CuI (102 mg,0.5 mmol) in isopropanol (4 mL) at 150° C. The reaction was purified byflash column chromatography on silica gel with gradient from 0% to 4%solution of (2 M NH₃ in MeOH) in CH₂Cl₂ to give the title product as ayellow amorphous solid. MS (ESI, pos ion.) m/z: 388 (M+1). MP: 225-227°C.

Example 18

(a) 4-Nitro-1H-benzoimidazol-2-ylamine. A solution of3-nitro-1,2-phenylenediamine (0.50 g, 3.26 mmol, Aldrich) and cyanogenbromide (0.38 g, 3.58 mmol, Aldrich) in EtOH (25 mL) was stirred for 24h. The resulting solid was filtered and air-dried to give the titleproduct as a reddish-brown solid. MS (ESI, pos. ion) m/z: 179 (M+1).

(b) N-(4-Nitro-1H-benzoimidazol-2-yl)acetamide. A mixture of4-nitro-1H-benzoimidazol-2-ylamine (0.13 g, 0.73 mmol) in aceticanhydride (10 mL) was heated at 80° C. for 3 h. The mixture was allowedto cool to room temperature and the precipitate was filtered, washedwith water and air dried to give the title product as a white solid. MS(ESI, pos. ion) m/z: 221 (M+1).

(c) N-(4-Amino-1H-benzoimidazol-2-yl)acetamide. A mixture of 10% Pd/C(0.040 g, Aldrich), N-(4-nitro-1H-benzoimidazol-2-yl)acetamide (0.090 g,0.41 mmol) and ETOH (6 mL) was purged with nitrogen and stirred under 1atmosphere H₂ for 18 h. The mixture was filtered through Celites andevaporated to yield the title product as a light yellow solid. MS (ESI,pos. ion) m/z: 191 (M+1).

(d)N⁴-[6-(4-Trifluoromethylphenyl)pyrimidin-4-yl]-1H-benzoimidazole-2,4-diamine.A solution of N-(4-amino-1H-benzoimidazol-2-yl)acetamide (0.067 g, 0.35mmol) and 4-chloro-6-(4-trifluoromethylphenyl)pyrimidine, Example 5(a),(0.103 g, 0.41 mmol) in ETOH (2 mL) was heated in a microwave at 175° C.with stirring for 15 min. The resulting yellow precipitate was filteredand purified by preparative HPLC (C 18 column, with a mobile phase of0.11% TFA in CH₃CN/H₂O, gradient from 10% CH₃CN to 90% over 20 min) togive the title compound as a white solid, MS (ESI, pos. ion) m/z: 371(M+1).

Example 19

N-{4-[6-(4-Trifluoromethylphenyl)pyrimidin-4-ylamino]-1H-benzoimidazol-2-yl}acetamide.The title compound was isolated from one of the fractions of thepreparative HPLC purification of Example 18(d) and was re-purified bypreparative HPLC (C8 column, with a mobile phase of 0.1% TFA inCH₃CN/H₂O, gradient from 20% CH₃CN to 80% over 20 min) to yield a whitesolid. MS (ESI, pos. ion) m/z: 413 (M+1).

Example 20

[(2-Morpholin-4-yl)quinolin-7-yl]-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]aminehydrochloride. A solution of(2-chloroquinolin-7-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine,Example 13(b), (150 mg, 0.37 mmol) in morpholine (0.65 mL, 7.4 mmol,Aldrich) was stirred and heated in a microwave at 200° C. for 10 min.The resulting bright yellow solid was precipitated from EtOAc andCH₂Cl₂, then dissolved in EtOAc (100 mL) and treated with 1 N HCl (50mL). The resulting bright yellow precipitate was collected byfiltration, washed with water (20 mL), EtOAc (20 mL) and air-dried toprovide the title product as a yellow amorphous solid. MS (ESI, pos.ion) m/z: 452 (M+1).

Example 21

(2-Methylaminoquinolin-7-yl)-[6-(4-trifluoro methylphenyl)pyrimidin-4-yl]amine dihydrochloride.(2-Chloroquinolin-7-yl)-[6-(4-trifluoromethyl-phenyl)pyrimidin-4-yl]amine,Example 13(b), (100 mg, 0.25 mmol) was dissolved in satd methylamine inEtOH [2 mL, prepared by bubbling methylaamine (Aldrich) into EtOH at 0°C.]. The solution was heated in a microwave at 160° C. for 20 min.Additional satd methylamine in EtOH (2 mL) was added and the reactionmixture was heated again in a microwave at 160° C. for 20 min. Themixture was concentrated in vacuo, redissolved in satd methylamine inEtOH (2 mL), and heated for an additional 20 min at 160° C. The mixturewas concentrated in vacuo and the residue suspended in 1 N HCl (20 mL)and EtOAc (50 mL). The suspension was shaken vigorously and the solidcollected by filtration, washed with water (20 mL), EtOAc (20 mL),hexane (20 mL) and air-dried. The solid was dissolved in MeOH, andconcentrated in vacuo to provide the title product as a yellow amorphoussolid. MS (ESI, pos. ion) m/z: 396 (M+1).

Example 22

(3-Methanesulfonylphenyl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine

Analogous to the procedure used to prepare Example 5(b),4-chloro-6-(4-trifluoromethylphenyl)pyrimidine, Example 5(a), (200 mg,0.77 mmol) and 3-methylsulphonylaniline hydrochloride (80 mg, 0.39 mmol,Acros) afforded a crude reaction product mixture, which was partitionedbetween EtOAc (100 mL) and 1 N NaOH (50 mL). The organic layer waswashed with 1 N NaOH (50 mL), water (50 mL), satd NaCl (20 mL), driedover Na₂SO₄, filtered and concentrated in vacuo. Purification by silicagel chromatography (9:1 CH₂Cl₂/EtOAc) provided the title product as awhite solid. MS (ESI, pos. ion) m/z: 394 (M+1). MP: 204-205° C.

Example 23

(a) (2-Methoxy-4-nitrophenyl)methan-1-ol. To a solution of2-methoxy-4-nitrobenzoic acid (2.0 g, 10 mmol, Aldrich) in THF (30 mL),magnetically stirred at 0° C. under N₂ in a round-bottomed flaskequipped with a reflux condenser, was added borane-THF complex (30 mL,30 mmol, 1.0 M in THF, Aldrich). The reaction mixture was stirred atreflux overnight. The reaction was quenched by the careful addition ofMeOH (5 mL), followed by 1 N NaOH (30 mL). The mixture was extractedwith EtOAc (2×50 mL), the combined organic extracts were washed withsatd NaCl, dried over Na₂SO₄, filtered and concentrated in vacuo to givethe title product. MS (ESI, neg. ion) m/z: 182 (M−1).

(b) 2-Methoxy-4-nitrobenzaldehyde. A mixture of(2-methoxy-4-nitrophenyl)-methan-1-ol (1.6 g, 8.9 mmol) and MnO₂ (15 g,180 mmol, Aldrich) in 1:1 hexane/CH₂Cl₂ (60 mL) was magnetically stirredat 40° C. for 3 h. The solid was removed by filtration and washed withCH₂Cl₂. The filtrate was concentrated in vacuo and the residue wasrecrystallized from EtOAc and hexane to give the title product. MS (ESI,neg. ion) z/z: 180 (M−1).

(c) 2-Hydroxy-4-nitrobenzaldehyde. To a solution of2-methoxy-4-nitrobenzaldehyde, (190 mg, 1.0 mmol) in CH₂Cl₂ (5 mL),magnetically stirred at −78° C. in a round-bottomed flask, was addedBBr₃ (0.19 mL, 2.0 mmol, Aldrich). The reaction mixture was allowed towarm to 25° C. and stirred at that temperature for 2 h. The reactionmixture was then cooled to −78° C., and treated with MeOH (5 mL). Themixture was allowed to warm to 25° C., stirred at that temperature for30 min, then concentrated in vacuo. Purification by silica gelchromatography (3:2 hexane/EtOAc) provided the title product. MS (ESI,neg. ion) m/z: 166 (M−1).

(d) (2S)-4-Nitro-2-oxiranylmethoxybenzaldehyde. A mixture of(2S)-(+)-glycidyl tosylate (1.1 g, 5.0 mmol, Aldrich),2-hydroxy-4-nitrobenzaldehyde (840 mg, 5.0 mmol) and K₂CO₃ (1.4 g, 10mmol) in DMF (5 mL) in a 100-mL, round-bottomed flask was stirred at100° C. for 30 min. The mixture was allowed to cool to room temperature,water (20 mL) was added, and the mixture was extracted with EtOAc (3×30mL). The combined extracts were washed with water (2×20 mL), satd NaCl(10 mL), dried over Na₂SO₄, and concentrated in vacuo. The crudematerial was purified by silica gel chromatography (80% EtOAc in hexane)to give the title product. MS (ESI, pos. ion) m/z: 224 (M+1).

(e) (2R)-(2,3-Dihydro-6-nitrobenzo[1,4]dioxin-2-yl)methanol. (Analogousto the procedure of Andrew, M.; Birch, A. M.; Bradley, P. A. Synthesis1999, 7, 1181-1187). To a solution of(2S)-4-nitro-2-oxiranylmethoxybenzaldehyde (730 mg, 3.3 mmol) in CH₂Cl₂(10 mL) in a 100-mL, round-bottomed flask was added 86%m-chloroperbenzoic acid (1.1 g, 6.4 mmol, Aldrich) at 0° C. The mixturewas allowed to warm to room temperature and stirred at that temperaturefor 18 h. The mixture was diluted with CH₂Cl₂ (20 mL), washed with 10%Na₂S₂O₃ (6 mL), aq NaHCO₃ (3×5 mL), satd NaCl (3 mL), dried over Na₂SO₄,and concentrated in vacuo. The crude material was stirred in MeOH (20mL) and 1 N NaOH (6.5 mL) for 16 h. Water (10 mL) was added, and themixture was extracted with EtOAc (3×10 mL). The combined organic phaseswere washed with satd NaCl, dried over Na₂SO₄, concentrated in vacuo,and the crude material was purified by silica gel chromatography (40%EtOAc in hexane) to give of the title product. MS (ESI, pos. ion) m/z:212 (M+1).

(f) (2R)-(6-Amino-2,3-dihydrobenzo[1,4]dioxin-2-yl)methanol. A mixtureof (2R)-(2,3-dihydro-6-nitrobenzo[1,4]dioxin-2-yl)methanol (120 mg, 0.56mmol) and 10% Pd/C (20 mg, Aldrich) in MeOH (5 mL) in a 100-mL,round-bottomed flask was stirred under 1 atmosphere of H₂ for 2 h. Thecatalyst was filtered off and washed with MeOH. The solvent was removedin vacuo to give the title product. MS (ESI, pos. ion) m/z: 182 (M+1).

(g)(2R)-{6-[6-(4-Trifluoromethylphenyl)pyrimidin-4-ylamino]-2H,3H-benzo[1,4]dioxin-2-yl}methanol.Analogous to the procedure described for the preparation of Example5(b), (2R)-(6-amino-2,3-dihydrobenzo[1,4]dioxin-2yl)methanol (100 mg,0.55 mmol) and 4-chloro-6-(4-trifluoromethylphenyl)-pyrimidine, Example5(a), (285 mg, 1.1 mmol) provided, after purification by silica gelchromatography (60% EtOAc/hexane), the title product as an amorphousyellow solid. MS (ESI, pos. ion) m/z: 404 (M+1).

Example 24

O₂N NH

(a) N-(2-Bromo-5-nitrophenyl)acetamide. A solution of2-bromo-5-nitroaniline (43 g, 0.20 mol, Aldrich) in glacial acetic acid(1.3 L), magnetically stirred at 25° C., was treated with aceticanhydride (20 mL, 0.21 mol). The reaction mixture was allowed to stir at25° C. overnight, then quenched by pouring into water (6 L). Theprecipitate was collected by filtration, washed with water, and dried invacuo to provide the title product as an off-white solid. MS (ESI, pos.ion) m/z: 259, 262 (M+1, M+3).

0²NoBr

(b) N-(2-Bromo-5-nitrophenyl)-N-(2-methyl-2-propenyl)acetamide. To aflame-dried round-bottomed flask, equipped with magnetic stirring and anaddition funnel, was added N-(2-bromo-5-nitrophenyl)acetamide (48 g,0.19 mol), potassium carbonate (103 g, 744 mmol) and anhydrous DMF (830mL). The resulting solution was stirred at 25° C. and treated dropwise,through the addition funnel, with a solution of 3-bromo-2-methylpropene(38 mL, 380 mmol, Aldrich) in anhydrous DMF (100 mL) over 45 min. Thereaction mixture was stirred at 25° C. overnight, then filtered andtreated with satd NaHCO₃. The organic layer was removed and the aqueouslayer was extracted with EtOAc (3×150 mL). The combined organic extractswere washed with water (4×70 mL), satd NaCl (70 mL), dried over MgSO₄,filtered and concentrated in vacuo to provide the title product as ayellow solid. MS (ESI, pos. ion) m/z: 313, 315 (M+1, M+3).

(c) 1-(3,3-Dimethyl-6-nitro-2,3-dihydroindol-yl)ethanone. To aflame-dried, round-bottomed flask, equipped with magnetic stirring, wasadded N-(2-bromo-5-nitrophenyl)-N-(2-methyl-2-propenyl)acetamide (55 g,0.18 mol), tetraethylammonium chloride hydrate (30.8 g, 186 mmol,Aldrich), sodium formate (14.4 g, 212 mmol, Aldrich), sodium acetate(36.3 g, 443 mmol) and anhydrous DMF (443 mL). The resulting solutionwas purged with N₂ and treated with palladium (II) acetate (3.97 g, 17.7mmol, Aldrich). The reaction mixture was stirred at 80° C. for 15 h, andthen allowed to cool to 25° C. and filtered through a pad of Celite®.The Celite® was washed with EtOAc and the combined filtrate was washedwith satd NaHCO₃ (500 mL). The aqueous layer was extracted with EtOAc(3×100 mL) and the combined organic extract was washed with water (4×100mL), satd NaCl (2×100 mL), dried over MgSO₄, filtered and concentratedin vacuo to provide the title product as a brown solid. MS (ESI, pos.ion) m/z: 235 (M+1).

(d)1-{3,3-Dimethyl-6-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]-2,3-dihydroindol-1-yl}ethanone.To a solution of 1-(3,3-dimethyl-6-nitro-2,3-dihydroindol-yl)ethanone(110 mg, 0.47 mmol) in ethyl ether (3 mL), magnetically stirred in around-bottomed flask at 0° C., was added tin (II) chloride dihydrate(0.67 g, 2.96 mmol, Aldrich) and concd HCl (0.3 mL). The reactionmixture was stirred at 0° C. for 10 min, allowed to warm to 25° C. thenstirred at that temperature overnight. The reaction mixture was washedwith 10 N NaOH (10 mL), extracted with EtOAc and concentrated in vacuo.Analogous to the procedure used to prepare Example 5(b), the crudeproduct and 4-chloro-6-(4-trifluoromethylphenyl)pyrimidine, Example5(a), (0.19 g, 0.75 mmol) provided, after purification by silica gelchromatography (3:2 hexanes/EtOAc), the title product. MS (ESI, pos.ion) m/z: 427 (M+1). MP: 227-230° C.

Example 25

(a) N-(2-Bromo-5-nitrophenyl)formamide. A mixture of2-bromo-5-nitroaniline (2 g, 9.2 mmol, Aldrich) and 85% formic acid (20mL, Aldrich) in a 50-mL, round-bottomed flask was heated at reflux for 3h. The reaction mixture was poured into cold water (75 mL) and theyellow precipitate was filtered, washed with water and dried in a vacuumoven at 60° C. overnight to provide the title compound as a yellowsolid. MS (ESI, pos. ion) m/z: 246 (M+1).

(b) 5-Nitrobenzothiazole. To a solution ofN-(2-bromo-5-nitrophenyl)formamide (2.1 g, 8.6 mmol) in hot ethanol (40mL) was added sodium sulfide (1.1 g, 13 mmol, Aldrich) and the mixturewas heated at reflux for 4 h. The solvent was evaporated in vacuo andthe residue was diluted with water and filtered. The pH of the filtratewas adjusted to 7 by the addition of 1 N HCl, the precipitate whichseparated was filtered, washed with water and dried in a vacuum oven at60° C. overnight to provide the title compound as a yellow solid. MS(ESI, pos. ion) m/z: 181 (M+1).

(c) 5-Aminobenzothiazole. To a solution of 5-nitrobenzothiazole (0.55 g,3.1 mmol) in ethanol (30 mL) was added 10% palladium on carbon (0.18 g,Aldrich). The reaction was stirred under 1 atmosphere of hydrogen for 5h. The reaction mixture was filtered through a pad of Celite®. Thefiltrate was concentrated to provide the title compound as an orangesolid. MS (ESI, pos. ion) m/z: 151 (M+1).

(d) Benzothiazol-5-yl-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine.Analogous to the procedure used to prepare Example 5(b),5-aminobenzothiazole (0.16 g, 1.1 mmol) and4-chloro-6-(4-trifluoromethylphenyl)pyrimidine, Example 5(a), (0.42 g,1.6 mmol) provided, after purification by silica gel chromatography (2:1hexanes/EtOAc), the title product as a light-yellow solid. MS (ESI, pos.ion) m/z: 373 (M+1). MP: 192.1-192.2° C.

Example 26

(1H-Benzoimidazol-4-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine.Analogous to the procedure used to prepare Example 5(b),4-chloro-6-(4-trifluoromethylphenyl)pyrimidine, Example 5(a), (690 mg,2.67 mmol) and 4-aminobenzimidazole (296 mg, 2.22 mmol, Astatech)afforded after purification by silica gel chromatography with gradientfrom 1% to 10% solution of (2 M NH₃ in MeOH) in CH₂Cl₂, the titlecompound as a yellow solid. MS (ESI, pos. ion.) m/z: 356 (M+1).

Example 27

(a) 2-(5-Aminopyridin-2-yloxy)ethanol. To a solution of2-(5-nitro-2-pyridyloxy)ethanol (1 g, 5.43 mmol, Lancaster) in EtOH (50mL) was added 10% palladium on carbon (0.2 g, Aldrich) and the mixturewas flushed with argon and then stirred under 1 atmosphere of H₂ for 15h. The reaction mixture was filtered through a pad of Celite®, thefiltrate was concentrated under vacuo and the residue purified by silicagel column chromatography (EtOAc) to provide the title compound as anoff-white solid. MS (ESI, pos. ion.) m/z: 155 (M+1).

(b)2-{5-[6-(4-Trifluoromethylphenyl)pyrimidin-4-ylaminolpyridin-2-yloxy}ethanol.4-Chloro-6-(4-trifluoromethylphenyl)pyrimidine, Example 5(a), (216 mg,0.83 mmol) was reacted with 2-(5-aminopyridin-2-yloxy)ethanol (130 mg,0.83 mmol) in EtOH (3 mL) in a fashion similar to that described inExample 5(b), to provide the title compound as a white powder. MS (ESI,pos. ion.) m/z: 377 (M+1). MP: 189.5-190.5° C.

Example 28

(a) 7-Amino-1H-indole-2-carboxylic acid ethyl ester. To a solution of7-nitro-1H-indole-2-carboxylic acid ethyl ester (5.0 g, 21.36 mmol,Acros) in MeOH (100 mL) was added 10% palladium on carbon (2.0 g,Aldrich) and the mixture was flushed with argon and then stirred under 1atmosphere of H₂ for 5 h. The reaction mixture was filtered through apad of Celite® and the filtrate was concentrated to provide the titlecompound as an off-white solid, which was used in the next step withoutfurther purification. MS (ESI, pos. ion.) m/z: 205 (M+1).

(b)7-[6-(4-Trifluoromethylphenyl)pyrimidin-4-ylamino]-1H-indole-2-carboxylicacid ethyl ester. 7-Amino-1H-indole-2-carboxylic acid ethyl ester (142mg, 0.69 mmol) was reacted with4-chloro-6-(4-trifluoromethylphenyl)-pyrimidine, Example 5(a), (183 mg,0.71 mmol) in EtOH (3 mL) in a fashion similar to that described inExample 5(b), to provide the title compound as a brown solid. MS (ESI,pos. ion.) m/z: 427 (M+1).

(c){7-[6-(4-Trifluoromethylphenyl)pyrimidin-4-ylamino]-1H-indol-2-yl}methanol.

To a solution of7-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]-1H-indole-2-carboxylicacid ethyl ester (285 mg, 0.67 mmol) in THF (2 mL) at 0° C. was added 1M solution of LiAlH₄ in THF (1.0 mL, Aldrich). The mixture was stirredat room temperature and the progress of the reaction was monitored bythin-layer chromatography. After completion of the reaction, to themixture was added Na₂SO₄.1H₂O (2 g), followed by the addition of MeOH (1mL) and EtOAc (20 mL) with stirring at 0° C. The stirring was continuedfor 5 min and the mixture was filtered through a pad of Celite®. Thefiltrate was concentrated under vacuo and the residue was purified bysilica gel column chromatography with gradient from 2% to 10% solutionof (2 M NH₃ in MeOH) in CH₂Cl₂ to afford the title compound as a yellowsolid. MS (ESI, pos. ion.) m/z: 385 (M+1). MP: 221-223° C.

Example 29

(a) 4-Chloro-6-phenylpyrimidine. To a 500-mL, round-bottomed flask wasadded 4,6-dichloropyrimidine (6.1 g, 41 mmol, Aldrich), phenylboronicacid (2.0 g, 16 mmol, Aldrich), acetonitrile (150 mL) and 0.40 M aqsodium carbonate (100 mL). The mixture was deoxygenated by sparging withN₂ for 15 min. The catalyst, Pd(PPh₃)₄ (1.9 g, 0.70 mmol, Strem), wasadded and the yellow mixture was heated at 90° C. for 15 h. The reactionmixture was cooled to room temperature and concentrated in vacuo toremove the acetonitrile. The residue was diluted with water (100 mL) andextracted with ethyl acetate (3×50 mL). The combined organic extractswere dried over Na₂SO₄, filtered and concentrated in vacuo. Purificationby silica gel chromatography (2:1 CH₂Cl₂/hexane) afforded the titlecompound as a white solid. MS (ESI, pos. ion) m/z: 191 (M+1).

(b) (2,3-Dihydrobenzoll, 4]dioxin-6-yl)-(6-phenylpyrimidin-4-yl)amine.Analogous to the procedure used to prepare Example 5(b),4-chloro-6-phenyl)pyrimidine, (0.20 g, 1.0 mmol) and2,3-dihydrobenzo[1,4]dioxin-6-ylamine (0.20 g, 1.0 mmol, Lancaster)afforded after purification by silica gel chromatography (1:1 ethylacetate/hexane) afforded the title compound as a purple solid. MS (ESI,pos. ion) m/z: 306 (M+1).

Example 30

(a) 4-Fluoro-6-[4-(trifluoromethyl)phenyl]pyrimidine. To a 500-mL,round-bottomed flask was added4-chloro-6-[4-trifluoromethyl)phenyl]pyrimidine, Example 5(a), (3.0 g,11 mmol), potassium fluoride (5.4 g, 93 mmol, Aldrich) and anhydrousDMSO (25 mL). The reaction mixture was stirred at 100° C. for 4 h undera N₂ atmosphere. The mixture was diluted with water (200 mL) andextracted with EtOAc (3×50 mL). The combined extracts were dried overNa₂SO₄, filtered and concentrated in vacuo. Purification by silica gelchromatography with gradient from 5% to 10% ethyl acetate in hexaneafforded the title compound as a white crystalline solid. MS (ESI, pos.ion) m/z: 243 (M+1).

(b)(3-Methylbenzo[d]isothiazol-5-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine.To a glass vial containing a magnetic stir bar was added4-fluoro-6-[4-(trifluoromethyl)phenyl]pyrimidine (0.10 g, 0.39 mmol),5-aminobenzotriazole (0.10 g, 0.42 mmol, Lancaster) and DMSO (1 mL). Thereaction mixture was stirred and heated in a microwave at 180° C. for 20min. The mixture was diluted with water (100 mL) and extracted withEtOAc (2×10 mL). The combined extracts were dried over Na₂SO₄, filteredand concentrated in vacuo. Purification by silica gel chromatography(1:1 ethyl acetate/hexane) afforded the title compound as a yellowsolid. MS (ESI, pos. ion) m/z: 387 (M+1).

Example 31

(a) 8-Benzyloxyquinolin-2-ylamine. To a 25-mL, round-bottomed flaskunder a N₂ atmosphere was added 2-amino-quinolin-8-ol (0.20 g, 1.3 mmol,Sigma) and DMF (8 mL). The mixture was cooled to 0° C. and NaH (0.06 g,1.5 mmol, Aldrich, 60% dispersion in oil) was added. After stirring for10 min at 0° C., benzyl bromide (0.16 mL, 1.4 mmol, Aldrich) was addedand the mixture was allowed to warm to room temperature. After stirringfor 23 h, the reaction was quenched with H₂O and extracted with EtOAc.The combined extracts were washed with 1 N NaOH (2×), H₂O and brine,dried over Na₂SO₄ and concentrated in vacuo to afford the title compoundas an off-white solid. MS (ESI, pos. ion) m/z: 251 (M+1).

(b)(8-Benzyloxyquinolin-2-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine

To an oven dried, 15-mL round-bottomed flask was added Pd(OAc)₂ (4 mg,0.02 mmol, Aldrich) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(12 mg, 0.020 mmol, Aldrich). The flask was carefully evacuated and thenbackfilled with N₂, twice. Toluene (4 mL) was added and the mixture wasstirred for 5 min at room temperature. To the mixture were then added4-chloro-6-(4-trifluoro-methylphenyl)pyrimidine, Example 5(a), (100 mg,0.40 mmol), 8-benzyloxy-quinolin-2-ylamine (100 mg, 0.40 mmol) and K₂CO₃(1.1 g, 8.0 mmol). The reaction vessel was again carefully evacuated andbackfilled with N₂, twice. The reaction was stirred for 16 h at 90° C.After cooling to room temperature, the reaction mixture was diluted withCH₂Cl₂/MeOH (3:1) and filtered. The filtrate was concentrated in vacuoonto silica gel and purified by silica gel chromatography with gradientfrom 0.3% to 1.5% solution of (2 M NH₃ in MeOH) in CH₂Cl₂. The titlecompound was isolated as an off-white solid. MS (ESI, pos. ion) m/z: 473(M+1).

(c) 2-[6-(4-Trifluoromethylphenyl)pyrimidin-4-ylamino]quinolin-8-ol. Toa round-bottomed flask containing(8-benzyloxyquinolin-2-yl)-[6-(4-trifluoro-methylphenyl)pyrimidin-4-yl]amine(0.050 g, 0.11 mmol) in MeOH (5 mL) and AcOH (0.5 mL) was addedpalladium [10 wt. % (dry basis) on activated carbon, wet, Degussa typeE101 NE/W, 0.022 g, Aldrich). The flask was carefully evacuated andbackfilled with H₂, twice. The reaction mixture was stirred under 1atmosphere H₂ for 24 h. The flask was then evacuated and backfilled withN₂, twice. The suspension was diluted with MeOH and filtered. Thefiltercake was washed with MeOH and MeOH/CH₂Cl₂ and the combinedfiltrates were concentrated in vacuo. The crude product was purified bypreparative HPLC. The fractions containing product were combined,concentrated in vacuo to remove the CH₃CN, neutralized with pH 7 buffer(Gibco BRL 20×SSC, 3.0 M NaCl and 0.3 M sodium citrate). The resultingprecipitate was collected by filtration and dried in vacuo to afford thetitle compound as a yellow solid. MS (ESI, pos. ion) m/z: 383 (M+1).

Example 32

(a) Quinolin-8-ylcarbamic acid ethyl ester. To a solution of8-aminoquinoline (2.5 g, 17 mmol, Aldrich) in pyridine (50 mL) was addedethyl chloroformate (2.0 mL, 20 mmol, Aldrich). The mixture was cooledto 0° C. and stirred for 30 min, then allowed to warm to roomtemperature and stirred at that temperature for 3 days. The mixture wasconcentrated in vacuo and diluted with satd NaHCO₃ and H₂O (1:1). Themixture was extracted with EtOAc (3×100 mL) and the combined extractswere washed with H₂O (100 mL), brine (100 mL), dried over Na₂SO₄ andconcentrated in vacuo to provide the title compound as a brown solid. MS(ESI, pos. ion) m/z: 217 (M+1).

(b) (1-Oxyquinolin-8-yl)carbamic acid ethyl ester. To a 100-mL,round-bottomed flask was added quinolin-8-ylcarbamic acid ethyl ester(3.6 g, 17 mmol), AcOH (14 mL) and 30% aq H₂O₂ (4.0 mL, Aldrich). Thereaction mixture was stirred at 65° C. for 3 h. Additional H₂O₂ (2.0 mL)was added and stirring was continued at 65° C. for 17 h. The reactionmixture was cooled to room temperature and diluted with H₂O (150 mL) andsatd NaHCO₃ (150 mL). Once the gas evolution had nearly subsided, themixture was extracted with EtOAc (3×100 mL). The combined extracts werewashed with aq NaHCO₃, brine, dried over Na₂SO₄, filtered and thefiltrate concentrated in vacuo. The crude product was eluted with EtOActhrough a plug of silica gel and concentrated in vacuo to afford thetitle compound as an orange solid. MS (ESI, pos. ion) m/z: 233 (M+1).

(c) (2-Chloroquinolin-8-yl)carbamic acid ethyl ester. To around-bottomed flask containing (1-oxy-quinolin-8-yl)carbamic acid ethylester (2.7 g, 12 mmol) in toluene (50 mL) was added SOCl₂ (1 mL, 14mmol, Aldrich). The reaction mixture was stirred at 75° C. for 5 h, thenallowed to cool to room temperature and concentrated in vacuo. Theresidue was diluted with satd NaHCO₃ (50 mL) and H₂O (50 mL) andextracted with EtOAc (2×100 mL). The combined extracts were washed withH₂O (100 mL), brine (100 mL), dried over Na₂SO₄ and concentrated invacuo onto silica gel. Purification by silica gel chromatography withgradient from 0% to 10% EtOAc in hexane, followed by recrystallizationfrom hexane afforded the title compound as a white solid. MS (ESI, pos.ion) m/z: 251 (M+1).

(d) 2-Chloroquinolin-8-ylamine. To a round-bottomed flask containing(2-chloroquinolin-8-yl)carbamic acid ethyl ester (0.28 g, 1.1 mmol) in2-methyl-2-propanol (25 mL) was added 10 N NaOH (15 mL). The mixture wasstirred at 70° C. for 2 days. The mixture was cooled to room temperatureand then diluted with satd NaHCO₃ and extracted with EtOAc. The aqueousphase was neutralized with conc. HCl and extracted with EtOAc. Thecombined extracts were washed with H₂O (2×), brine, dried over Na₂SO₄and concentrated in vacuo onto silica gel.

Purification by silica gel chromatography with gradient from 0% to 10%EtOAc in hexane afforded the title compound as a pale yellow solid. MS(ESI, pos. ion) m/z: 179 (M+1).

(e)(2-Chloroquinolin-8-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine.To a glass vial containing a magnetic stir bar was added4-fluoro-6-(4-trifluoromethylphenyl)pyrimidine, Example 29(a), (0.39 g,1.6 mmol), 2-chloro-quinolin-8-ylamine (0.14 g, 0.79 mmol) and anhydrousDMSO (1 mL). The reaction mixture was stirred and heated in a microwaveat 170° C. for 20 min. The mixture was diluted with satd NaHCO₃ andextracted with EtOAc. The combined extracts were washed with H₂O, brine,dried over Na₂SO₄, filtered and concentrated in vacuo onto silica gel.Purification by silica gel chromatography with gradient from 3% to 18%EtOAc in hexane afforded the title compound as a white solid. MS (ESI,pos. ion) m/z: 401 (M+1). MP: 240° C.

Example 33

N⁸-[6-(4-Trifluoromethylphenyl)pyrimidin-4-yl]quinoline-2,8-diamine. Toa round-bottomed flask containing(2-chloroquinolin-8-yl)-[6-(4-trifluoromethyl-phenyl)pyrimidin-4-yl]amine,Example 32(e), (0.090 g, 0.22 mmol) in DMSO (10 mL) was added NaN₃ (0.53g, 8.1 mmol, Aldrich). The reaction mixture was stirred at 105° C. for 4days and then at 115° C. for 1 day. The reaction mixture was cooled toroom temperature and then diluted with H₂O and extracted with EtOAc. Thecombined extracts were washed with H₂O (3×), brine, dried over Na₂SO₄,and concentrated in vacuo to afford a tan solid. The tan solid wasdissolved in toluene (5 mL), triphenylphosphine (0.12 g, 0.44 mmol,Aldrich) was added with stirring at room temperature and the mixture wasstirred at reflux for 8 h. After cooling to room temperature, themixture was concentrated in vacuo to remove the toluene. To the residuewas added AcOH/H₂O (2:1, 7 mL) and the mixture was stirred at 55° C. for1 day. The reaction mixture was cooled to room temperature and thendiluted with satd NaHCO₃ (75 mL) and extracted with EtOAc (2×75 mL). Thecombined extracts were washed with brine, dried over K₂CO₃ andconcentrated in vacuo. The residue was dissolved in EtOAc andconcentrated in vacuo onto silica gel. Purification by silica gelchromatography with gradient from 20% to 60% EtOAc in hexane affordedthe title compound as a yellow solid. MS (ESI, pos. ion) m/z: 382 (M+1).MP: 211-213° C.

Example 34

(a) Spiro[cyclopropane-1,3′-indoline]. To a solution of3-(2-bromoethyl)indole (5 g, 22.31 mmol, Aldrich) in anhydrous CH₃CN(100 mL) was added oven dried K₂CO₃ (20 g, 144.7 mmol)) and the mixturewas heated under reflux with stirring for 10 h. The mixture was cooledto room temperature, filtered and the filter cake was washed with EtOH(50 mL). The combined filtrate was then treated with NaBH4 (300 mg, 7.93mmol)) and stirred for 3 h at room temperature. The solvents wereremoved in vacuo and the residue was partitioned between water (160 mL)and EtOAc (60 mL). The organic layer was extracted with 0.5N aq HCl (30mL×2). The acid layer was then basified with 28% aq NH₄OH and thenextracted with EtOAc. The combined organic extracts were washed withbrine, dried over Na₂SO₄ and concentrated to give the title compound asa colorless oil. MS (ESI, pos. ion) m/z: 146 (M+1).

(b) 6′-Nitrospiro[cyclopropane-1,3′-indoline].Spiro[cyclopropane-1,3′-indoline] (1.8 g, 12.4 mmol) was added dropwiseover 20 min into a solution of NaNO₃ (1.3 g, 15.3 mmol) in concd H₂SO₄(30 mL) with stirring and cooling (−5 to −10° C.). The reaction mixturewas stirred with cooling for another 40 min and poured onto crushed ice(200 g). The resulting mixture was basified with 28% aq NH₄OH withcooling and extracted with EtOAc. The combined organic extracts werewashed with brine, dried over Na₂SO₄ and concentrated in vacuo to givethe desired product as a dark gray solid. MS (ESI, pos. ion) m/z: 191(M+1).

(c) 1′-Acetyl-6′-nitrospirolcyclopropane-1,3′-indolinel. Acetyl chloride(1.1 g, 14 mmol) was added dropwise to a suspension of NaHCO₃ (5 g, 59.5mmol) in a solution of 6′-nitrospiro[cyclopropane-1,3′-indoline] (2.6 g,13.7 mmol) in dichloromethane (200 mL) with vigorous stirring at roomtemperature. The reaction mixture was stirred for 2 h at roomtemperature and filtered. The filtrate was concentrated in vacuo and theresidue purified by flash chromatography on silica gel with gradientfrom 75% to 80% solution of EtOAc in hexane to give the title compound.MS (ESI, pos. ion) m/z: 233 (M+1).

(d) {1′-Acetylspiro[cyclopropane-1,3′-indolin-6′-yl]}amine. To asolution of 1′-acetyl-6′-nitrospiro[cyclopropane-1,3′-indoline] (2 g,8.61 mmol) in EtOH (200 mL) was added 10% palladium on carbon (0.1 g,Aldrich) and the mixture was flushed with argon and then stirred under 1atmosphere of H₂ for 1.5 h. The reaction mixture was filtered through apad of Celites and the filtrate was concentrated to provide the titlecompound as white solid. MS (ESI, pos. ion) m/z: 203 (M+1).

(e){1′-Acetylspiro[cyclopropane-1,3′-indolin-6′-yl]}-[6-(4-trifluoromethyl-phenyl)pyrimidin-4-yl]amine.A mixture of 4-chloro-6-(4-trifluoromethyl-phenyl)pyrimidine, Example5(a), (0.138 g, 0.53 mmol) and{1′-acetylspiro-[cyclopropane-1,3′-indolin-6′-yl]}amine (0.119 g, 0.58mmol) in DMSO (1 mL) was stirred and heated in a microwave at 180° C.for 10 min. The mixture was diluted with water and extracted withCH₂Cl₂. The combined extracts were dried over Na₂SO₄, filtered andconcentrated in vacuo. Purification of the residue by silica gelchromatography with gradient from 0% to 40% solution of MeOH in CH₂Cl₂afforded the title compound as a yellow amorphous solid. MS (ESI, pos.ion) m/z: 425 (M+1).

Example 35

{Spirolcyclopropane-1,3′-indolin-6′-yl]}-[6-(4-trifluoromethylphenyl)-pyrimidin-4-yl]amine. A mixture of{1′-acetylspiro[cyclopropane-1,3′-indolin-6′-yl]}-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine,Example 34(e), (0.043 g, 0.10 mmol), 5 N of HCl (aq) (3.0 mL) and THF(1.0 mL) was stirred and heated at reflux for 3 h. The mixture wascooled to room temperature, basified with 10 N aq NaOH to pH˜10 andextracted with CH₂Cl₂. The combined extracts were washed with water,dried over Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 383 (M+1).

Example 36

(a) 2,3-Dimethyl-1H-indol-7-ylamine. A solution of2,3-dimethyl-7-nitroindole (500 mg, 2.6 mmol, Acros) in MeOH (25 mL) wasplaced under N₂ and treated with 10% palladium on carbon (281 mg,Aldrich). The suspension was purged with N₂ and magnetically stirredunder 1 atmosphere H₂ for 16 h. The reaction mixture was filteredthrough a pad of Celite® and the filtrate was concentrated to providethe title compound as a brown amorphous solid. MS (ESI, pos. ion) m/z:161 (M+1).

(b)(2,3-Dimethyl-1H-indol-7-yl)-[6-(4-(trifluoromethylphenyl)pyrimidin-4-yl]amine.

Analogous to the procedure used to prepare Example 5(b),4-chloro-6-(4-trifluoromethylphenyl)pyrimidine, Example 5(a), (240 mg,93 mmol) and 2,3-dimethyl-1H-indol-7-ylamine (150 mg, 0.93 mmol)provided after purification by preparative HPLC, the title compound as abrown amorphous solid. MS (ESI, pos. ion) m/z: 383 (M+1).

Example 37

(a) 1H-Indol-7-ylamine. The title compound was prepared by the methoddescribed in Example 36(a) from 7-nitroindole (500 mg, 2.6 mmol,Lancaster) to give a green amorphous solid. MS (ESI, pos. ion) m/z: 133(M+1).

(b) (1H-Indol-7-yl)-[6-(4-trifluoromethylphenylipyrimidin-4-yl)amine.Analogous to the procedure used to prepare Example 5(b),4-chloro-6-(4-trifluoromethylphenyl)pyrimidine, Example 5(a), (0.588 g,2.28 mmol) and 1H-indol-7-ylamine (150 mg, 1.13 mmol) provided the titlecompound as a brown amorphous solid. MS (ESI, pos. ion) m/z: 355 (M+1).

Example 38

(a) 2-Methyl-1H-benzoimidazol-4-ylamine. The title compound was preparedby the method described in Example 36(a) from7-nitro-2-methylbenzimidazole (0.3 g, 1.6 mmol, Tyger Sci.) to give abrown amorphous solid. MS (ESI, pos. ion) m/z: 148 (M+1).

(b)(2-Methyl-1H-benzoimidazol-4-yl)-[6-(4-trifluoromethyl)phenyl)pyrimidin-4-yl]amine.Analogous to the procedure used to prepare Example 5(b),4-chloro-6-(4-trifluoromethylphenyl)pyrimidine, Example 5(a), (227 mg,0.88 mmol) and 7-amino-2-methylbenzimidazole (150 mg, 0.88 mmol)provided the title compound as a light-yellow crystalline solid. MS(ESI, pos. ion) m/z: 370 (M+1).

Example 39

(1-Methyl-1H-benzoimidazol-4-yl)-[6-(4-trifluoromethyl)phenyl)pyrimidin-4-yl]amine.Analogous to the procedure used to prepare Example 5(b),4-chloro-6-(4-trifluoromethylphenyl)pyrimidine, Example 5(a), (227 mg0.88 mmol) and 7-amino-1-methyl-N-benzimidazole (350 mg, 0.88 mmol,Aldrich) provided, after purification by silica gel columnchromatography with eluent 10% solution of (2M NH₃ in MeOH) in CH₂Cl₂,the title compound as a light-yellow amorphous solid. MS (ESI, pos. ion)m/z: 371.2 (M+1).

Example 40

(a) 3-Chloro-1H-indol-7-ylamine. Analogous to the procedure used toprepare Example 16(b), 3-chloro-7-nitroindole (0.15 g, 0.76 mmol,UbiChem Res.) was reduced with iron dust (0.635 g, 11.3 mmol, Aldrich)to give the title compound as a yellow amorphous solid. MS (ESI, pos.ion) m/z: 167 (M+1).

(b)7-[6-(4-Trifluoromethylphenyl]pyrimidin-4-ylamino]-1,3-dihydroindol-2-one.Analogous to the procedure used to prepare Example 5(b),4-chloro-6-(4-trifluoromethylphenyl)pyrimidine, Example 5(a), (172 mg,0.66 mmol) and 3-chloro-1H-indol-7-ylamine (110 mg, 0.66 mmol) affordedthe title compound as a brown amorphous solid. MS (ESI, pos. ion) m/z:371 (M+1).

ADDITIONAL EXAMPLES

Following the procedures described above in Scheme 1, or with slightmodifications thereof, and following procedures familiar to one ofordinary skill in the art, the following examples were prepared fromcommercially available reagents: MS (ESI, Melting Example Structure pos.ion) m/z Point ° C. 41

374 (M + 1) 167-168 42

355 (M + 1) 231-232 43

355 (M + 1) 222-224 44

355 (M + 1) 183-185 45

372 (M + 1) 230-232 46

343 (M + 1) 241-242 47

355 (M + 1) 227-229 48

343 (M + 1) 194-196 49

345 (M + 1) 250-252 50

367 (M + 1) 262-263 51

304 (M + 1) 166 52

361 (M + 1) 237 53

334 (M + 1) 184-187 54

343 (M + 1) 238-240 55

387 (M + 1) 219.5-220.5 56

344 (M + 1) 154-156 57

364 (M + 1) 148-150 58

347 (M + 1) 123-127 59

362 (M + 1) 130-132 60

330 (M + 1) 159-160 61

418 (M + 1) 172-175 62

350 (M + 1) 193-196 63

384 (M + 1) 178-180 64

330 (M + 1) 117-119 65

364 (M + 1) 144-146 66

373 (M + 1) 236-238 67

355 (M + 1) amorphous 68

316 (M + 1) 184-186 69

373 (M + 1) amorphous 70

366 212-213 71

351 134-135 72

367 268-269 73

367 162-163 74

367 238-239 75

356 224-226 76

366 232-233 77

372 168

Example 78

(a) 3-(4-tert-Butylphenyl)-4-oxo-4-phenylbutyric acid ethyl ester.(Analogous to the procedure of EP 0 469 992 B 1). In a round-bottomedflask was placed 60% dispersion of NaH in mineral oil (264 mg, 6.6 mmol,Aldrich) and the oil was washed with hexane (2×). To this flask wasadded a solution of 2-(4-tert-butylphenyl)-1-phenylethanone (1.5 g, 5.9mmol, J. Am. Chem. Soc. 1997, 119, 12382) in DMSO (30 mL) with stirringat 0° C. The mixture was stirred at room temperature for 1 h, ethylchloroacetate (0.6 mL, 0.7 g, 6.0 mmol, Aldrich) was then added and thestirring was continued for 18 h. The reaction mixture was quenched with1M aq H₃PO₄, diluted with EtOAc (50 mL), washed with satd aq NaHCO₃ andbrine, dried over Na₂SO₄, filtered and concentrated to give the titlecompound. MS (ESI, pos. ion) m/z: 339 (M+1).

(b) 5-(4-tert-Butylphenyl)-6-phenyl-4,5-dihydro-2H-pyridazin-3-one. To asolution of 3-(4-tert-butylphenyl)-4-oxo-4-phenylbutyric acid ethylester (1.81 g, 5.4 mmol) in dioxane (5 mL) was added hydrazine hydrate(0.346 g, 10.8 mmol, Aldrich) and the mixture was heated under refluxwith stirring overnight. The reaction mixture was cooled to roomtemperature, diluted with EtOAc (50 mL) and washed with 0.5% aq H₃PO₄,satd NaHCO₃ and brine, dried over Na₂SO₄, filtered and concentrated togive the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 307(M+1).

(c) 5-(4-tert-Butylphenyl)-6-phenylpyridazin-3-ol.5-(4-tert-Butylphenyl)-6-phenyl-4,5-dihydro-2H-pyridazin-3-one (1.15 g,3.8 mmol) was dissolved in glacial AcOH (5 mL) and heated to 60° C.Bromine (722 mg, 4.5 mmol) was added dropwise and the mixture was heatedat 60° C. with stirring for 10 min. The reaction mixture was cooled toroom temperature, diluted with EtOAc (50 mL) and washed with satd aqNaHCO₃ (3×). The organic layer was dried over Na₂SO₄, filtered andconcentrated to give the title compound, which was used in the next stepwithout additional purification. MS (ESI, pos. ion) m/z: 305 (M+1).

(d) 4-(4-tert-Butylphenyl)-6-chloro-3-phenylpyridazine.5-(4-tert-Butylphenyl)-6-phenylpyridazin-3-ol (549 mg, 1.8 mmol) wasdissolved in POCl₃ (3 mL) and heated at 100° C. with stirring overnight.The POCl₃ was removed in vacuo and the residue was dissolved in EtOAcand washed with satd aq NaHCO₃ (2×). The organic layers were combined,dried over Na₂SO₄, filtered and the solvent was evaporated in vacuo togive the title compound. MS (ESI, pos. ion) m/z: 323 (M+1).

(e)Benzothiazol-6-yl-[5-(4-tert-butylphenyl)-6-phenylpyridazin-3-yl]amine.Analogous to the procedure used to prepare Example 5(b),4-(4-tert-butylphenyl)-6-chloro-3-phenylpyridazine (95 mg, 0.3 mmol) and6-aminobenzothiazole (44 mg, 0.3 mmol, Lancaster) afforded the titlecompound as a white crystalline solid. MS (ESI, pos. ion) m/z: 437(M+1). MP: 293-295° C.

Example 79

[5-(4-tert-Butylphenyl)-6-phenyl-pyridazin-3-yl]-(1H-indol-5-yl)-amine.Analogous to the procedure used to prepare Example 5(b),4-(4-tert-butylphenyl)-6-chloro-3-phenylpyridazine, Example 78(d), (95mg, 0.3 mmol) and 5-aminoindole (39 mg, 0.3 mmol, Aldrich) afforded thetitle compound as a light-yellow crystalline solid. MS (ESI, pos. ion)m/z: 419 (M+1). MP: 138-140° C.

Example 80

[5-(4-tert-Butylphenyl)-6-phenylpyridazin-3-yl]-(2,3-dihydrobenzo[1,4]-dioxin-6-yl)amine.Analogous to the procedure used to prepare Example 5(b),4-(4-tert-butyl-phenyl)-6-chloro-3-phenylpyridazine, Example 78(d), (155mg, 0.5 mmol) and 1,4-benzodioxan-6-amine (80 mg, 0.5 mmol, Aldrich) togive the product as a light yellow crystalline solid. MS (ESI, pos. ion)m/z: 438 (M+1).

Example 81

(a) Potassium (Z)-3-(4-trifluoromethylphenyl)-3-cyanopropenoate.(Analogous to the procedure of Dan, W. D. and Blum, D. M. J. Org. Chem.1993, 58, 7916-7917). Glyoxylic acid monohydrate (111.86 g, 1.22 mol,Aldrich) was added portion-wise to a suspension of potassium carbonate(284.4 g, 2.06 mol) in methanol (1.6 L) with stirring and cooling with awater bath. To the light-brown suspension was then added4-trifluoromethylphenylacetonitrile (150 g, 0.81 mol, Aldrich) in smallportions, the mixture was stirred for 5 h at room temperature, and theresulting thick solid precipitate was filtered and washed withdichloromethane. Concentration of the filtrate to a 600 mL volume led tothe precipitation of additional amount of solid, which was filtered andwashed with dichloromethane. The solids were combined and then suspendedin cold water (4 L) to remove the excess of potassium carbonate. Theprecipitate was filtered, washed with water and air-dried to provide thetitle compound as a white solid, which was used in the next step withoutadditional purification. MS (ESI, pos. ion) m/z: 279 (M).

(b) 4-Trifluoromethylphenylmaleic anhydride. (Analogous to the procedureof Dan, W. D. and Blum, D. M. J. Org. Chem. 1993, 58, 7916-7917).Potassium (Z)-3-(4-trifluoromethylphenyl)-3-cyanopropenoate (100 g, 358mmol) was dissolved in 88% formic acid (600 mL, Aldrich) containingconcentrated sulfuric acid (45 mL) and the mixture heated at reflux for3 h. The reaction mixture was then cooled and poured into ice water (1L). The resulting solid was filtered, washed with water and air dried togive the title compound as a pale-yellow solid, which was used in thenext step without additional purification. MS (ESI, pos. ion) m/z: 243(M+1).

(c) 4-(4-Trifluoromethylphenyl)-1,2-dihydropyridazine-3,6-dione.(Analogous to the procedure of Augustin, M. and Reinemann, P. Z. Chem.1973, 13, 12-13). 4-Trifluoromethylphenylmaleic anhydride (57.2 g, 235.8mmol) was added to a mixture of water (325 mL) and acetic acid (88 mL),followed by the drop-wise addition of hydrazine hydrate (11.44 mL, 235.8mmol, Aldrich) with stirring at room temperature. To the resultingpale-yellow suspension was then added drop-wise concentrated sulphuricacid (177 mL) with stirring and cooling in an ice bath, which led to theformation of a thick paste. The reaction mixture was heated at 100-115°C. for 3 h with stirring, and then cooled in an ice bath. Theprecipitate was washed with water until the filtrate showed neutral pH,and then was washed with diethyl ether (2×100 mL) and air-dried to givethe title compound as a white solid, which was used in the next stepwithout additional purification. MS (ESI, pos. ion) m/z: 257 (M+1).

(d) 3,6-Dichloro-4-(4-trifluoromethylphenyl)pyridazine. (Analogous tothe procedure of Augustin, M. and Reinemann, P. Z. Chem. 1973, 13,12-13). A mixture of4-(4-trifluoromethylphenyl)-1,2-dihydropyridazine-3,6-dione (25.6 g, 100mmol) and phosphorus oxychloride (192 mL) was heated under reflux for 2h with stirring under nitrogen atmosphere. The reaction mixture wascooled to room temperature and poured in small portions withenergetically stirring into a mixture of water and crushed ice (2.6 L).The product separated as a white precipitate, which was filtered, washedwith water (3×50 mL), dried under vacuo and recrystallized fromdioxane/methanol to give the title compound as a white solid. MS (ESI,pos. ion) m/z: 293 (M+1).

(e)Benzothiazol-6-yl-[6-chloro-5-(4-trifluoromethylphenyl)pyridazin-3-yl]amine.(Analogous to the procedure of JP02169579). To a solution of3,6-dichloro-4-(4-trifluoromethylphenyl)pyridazine (1.465 g, 5 mmol) and6-aminobenzothiazole (0.751 g, 5 mmol, Lancaster) in 1-butanol (6 mL)was added 37% hydrochloric acid (0.49 mL, 5 mmol) and the mixture heatedat 75° C. for 18 h with stirring under nitrogen atmosphere. The reactionmixture was cooled to room temperature, diluted with ethyl acetate (200mL) and water (300 mL), and stirred for 15 min at 60° C. The mixture wascooled to room temperature, the organic layer was separated and thenwashed with 1N hydrochloric acid (2×50 mL) and water (50 mL), dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelchromatography with ethyl acetate/hexane (2:3) to give the titlecompound as an yellow solid. MS (ESI, pos. ion) m/z: 407 (M+1). MP:206.3° C. (with decomposition).

Example 82

Benzothiazol-6-yl-[6-(2-naphthyl)-5-(4-trifluoromethylphenyl)pyridazin-3-yl]amine. (Ph₃P)₂PdCl₂ (0.026 g, 0.038 mmol, Strem) was added to a mixtureofbenzothiazol-6-yl-[6-chloro-5-(4-trifluoromethylphenyl)pyridazin-3-yl]amine(0.203 g, 0.5 mmol, Example 81(e), 2-naphthaleneboronic acid (0.129 g,0.75 mmol, Aldrich), Na₂CO₃ (0.053 g, 0.5 mmol), dimethoxyethane (1.4mL), EtOH (0.4 mL) and water (0.6 mL). The reaction mixture was heatedin a microwave at 120° C. for 15 min with stirring under nitrogen. Thereaction mixture was cooled to room temperature, diluted with ethylacetate (50 mL), washed with 1N NaOH (20 mL) and water (2×20 mL), driedover Na₂SO₄ and concentrated in vacuo.

The residue was purified by silica gel chromatography with ethylacetate/hexane (1:1) to give the title compound as an yellow amorphoussolid. MS (ESI, pos. ion) m/z: 499 (M+1).

ADDITIONAL EXAMPLES

Following the procedures described above in Scheme 2, or with slightmodifications thereof, and following procedures familiar to one ofordinary skill in the art, the following examples were prepared fromcommercially available 6-aminobenzothiazole: MS (ESI, Melting ExampleStructure pos. ion) m/z Point ° C. 83

449 (M + 1) 272 84

467 (M + 1) 269 85

517 (M + 1) 243 86

450 (M + 1) amorphous 87

450 (M + 1) amorphous

Example 88

[6-Chloro-5-(4-trifluoromethylphenyl)pyridazin-3-yl]-[quinolin-7-yl]amine.(Analogous to the procedure of WO 178270). A mixture of3,6-dichloro-4-(4-trifluoromethylphenyl)pyridazine, Example 81(d), (2.0g, 6.8 mmol), 7-amino-quinoline (984 mg, 6.8 mmol) and ZnCl₂ (980 mg,3.4 mmol) was heated in a microwave with stirring at 220° C. for 20 min.The reaction mixture was cooled to room temperature, a second portion of3,6-dichloro-4-(4-trifluoromethylphenyl)pyridazine (2.0 g, 6.8 mmol),was added and the mixture was heated again in microwave at 220° C. for40 min. The reaction mixture was cooled to room temperature, dilutedwith EtOAc (50 mL) and washed with H₂O (3×). The organic layer was driedover Na₂SO₄, filtered and the solvent evaporated in vacuo. The residuewas purified by preparative thin layer chromatography, eluting withMeOH:CH₂Cl₂ (1:39), to give the title compound as a light-yellow powder.MS (ESI, pos. ion) m/z: 401 (M+1).

Example 89

[6-(4-Methoxyphenyl)-5-(4-trifluoromethylphenyl)pyridazin-3-yl]-[quinolin-7-yl]amine.To a solution of[6-chloro-5-(4-trifluoromethylphenyl)pyridazin-3-yl]-[quinolin-7-yl]amine,Example 88, (100 mg, 0.3 mmol) in dioxane (2 mL) was added4-methoxyphenylboronic acid (46 mg, 0.3 mmol, Aldrich), followed by theaddition of 2M aq Na₂CO₃ (0.2 mL, 0.4 mmol) and Pd[PPh₃]₄ (35 mg, 0.03mmol, Aldrich). The mixture was flushed with N₂ and heated under at 100°C. under N₂ atmosphere for 24 h. The reaction mixture was cooled to roomtemperature, additional amounts of 2M aq Na₂CO₃ (0.2 mL, 0.4 mmol),4-methoxyphenyl-boronic acid (46 mg, 0.3 mmol) and Pd[PPh₃]₄ (35 mg,0.03 mmol) were added and the mixture was heated at 100° C. withstirring under N₂ atmosphere for 4 h. The reaction mixture was cooled toroom temperature, diluted with EtOAc (50 mL) and washed with 5% Na₂CO₃.The organic layer was dried over Na₂SO₄, filtered and the solventevaporated in vacuo. The residue was purified by column chromatography,eluting with MeOH:CH₂Cl₂ (1:19), to give the title compound as a tancrystalline solid. MS (ESI, pos. ion) m/z: 473 (M+1). MP: 215-217° C.

Example 90

5-Chloro-2-fluoro-4-(4-trifluoromethyl-phenyl)-pyridine.

This compound was prepared analogous to Example 5(a) using5-chlroro-2-fluoro-4-iodopyridine (0.64 g, 2.5 mmol, Asymchem),4-(trifluoromethyl)-benzeneboronic acid (0.52 g, 2.8 mmol, Avocado),tetrakis(triphenylphosphine)-palladium(0) (0.29 g, 0.25 mmol, Aldrich)and aqueous sodium carbonate (0.29 g in 10 mL of water) in toluene (10mL). After ISCO purification (EtOAc/hexanes=1:99 to 1:9 in 30 min), thetitle compound was isolated as a white solid. MS m/z: 276 (M+1).

[5-Chloro-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-quinolin-7-yl-amine.This compound could be prepared by the method described in Example 6(d)from 5-chloro-2-fluoro-4-(4-trifluoromethyl-phenyl)-pyridine and7-aminoquinoline by microwave in a Smith Synthesizer (PersonalChemistry) at 180° C. for 20 min. The product will be isolated usingflash chromatography.

Example 91

(a) 4,6-Diiodo-pyrimidine

A mixture of 4,6-dichloro-pyrimidine (1.0 g, 6.70 mmol.), NaI (1.36 g,9.00 mmol), and hydriodic acid (20 mL, 151.4 mmol.) was heated at 40° C.for 1 h and stirred at room temperature for additional 20 h. Thereaction mixture was basified with 10 N NaOH aqueous (18 mL). Theresulting precipitate was filtered, washed with water, and dried underhigh vacuo to give a light-yellow solid. MS (ESI, pos. ion) m/z: 332(M+1).

(b) (6-Iodo-pyrimidin-4-yl)-quinolin-7-yl-amine

This compound could be prepared from 4,6-diiodo-pyrimidine and7-aminoquinoline in the presence of K₂CO₃ and DMF.

(c)4-[6-(Quinolin-7-ylamino)-pyrimidin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester

This compound could be prepared from(6-iodo-pyrimidin-4-yl)-quinolin-7-yl-amine and4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester via Suzuki coupling reaction.

(d)Quinolin-7-yl-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyrimidin-4-yl)-amineThis compound could be prepared from4-[6-(quinolin-7-ylamino)-pyrimidin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester in the presence of TFA and CH₂Cl₂.

(e)[6-(1-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyrimidin-4-yl]-quinolin-7-yl-amine

This compound could be prepared fromquinolin-7-yl-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyrimidin-4-yl]-amineand formaldehyde in the presence of sodium triacetoxyborohydride andMeCN.

Example 92

(a) (6-Chloro-pyrimidin-4-yl)-quinolin-7-yl-amine

This compound could be prepared from 4,6-dichloro-pyrimidine and7-aminoquinoline in the presence of K₂CO₃ and DMF.

(b)Quinolin-7-yl-[6-(4-trifluoromethyl-piperidin-1-yl)-pyrimidin-4-yl]-amineThis compound could be prepared from(6-chloro-pyrimidin-4-yl)-quinolin-7-yl-amine and4-trifluoromethyl-piperidine in the presence of K₂CO₃ and DMF.

(c) 16-(4-Phenyl-piperazin-1-yl)-pyrimidin-4-yl]-quinolin-7-yl-amine

This compound could be prepared from(6-chloro-pyrimidin-4-yl)-quinolin-7-yl-amine and I-phenyl-piperazine inthe presence of K₂CO₃ and DMF.

Capsaicin-Induced Ca²⁺ Influx in Primary Dorsal Root Ganglion Neurons

Embryonic 19 day old (E19) dorsal root ganglia (DRG) were dissected fromtimed-pregnant, terminally anesthetized Sprague-Dawley rats (CharlesRiver, Wilmington, Mass.) and collected in ice-cold L-15 media (LifeTechnologies, Grand Island, N.Y.) containing 5% heat inactivated horseserum (Life Technologies). The DRG were then dissociated into singlecell suspension using a papain dissociation system (WorthingtonBiochemical Corp., Freehold, N.J.). The dissociated cells were pelletedat 200×g for 5 min and re-suspended in EBSS containing 1 mg/mL ovomucoidinhibitor, 1 mg/mL ovalbumin and 0.005% DNase. Cell suspension wascentrifuged through a gradient solution containing 10 mg/mL ovomucoidinhibitor, 10 mg/mL ovalbumin at 200×g for 6 min to remove cell debris;and filtered through a 88-μm nylon mesh (Fisher Scientific, Pittsburgh,Pa.) to remove any clumps. Cell number was determined with ahemocytometer and cells were seeded into poly-ornithine 100 μg/mL(Sigma) and mouse laminin 1 μg/mL (Life Technologies)-coated 96-wellplates at 10×10³ cells/well in complete medium. The complete mediumconsists of minimal essential medium (MEM) and Ham's F 12, 1:1,penicillin (100 U/mL), and streptomycin (100 μg/mL), and nerve growthfactor (10 ng/mL), 10% heat inactivated horse serum (Life Technologies).The cultures were kept at 37° C., 5% CO₂ and 100% humidity. Forcontrolling the growth of non-neuronal cells, 5-fluoro-2′-deoxyuridine(75 μM) and uridine (180 μM) were included in the medium. Activation ofVR1 was achieved in these cellular assays using either a capsaicinstimulus (ranging from 0.01-110 μM) or by an acid stimulus (addition of30 mM Hepes/Mes buffered at pH 4.1). Compounds were also tested in anassay format to evaluate their agonist properties at VR1. The activationof VR1 is followed as a function of cellular uptake of radioactivecalcium (⁴⁵Ca²⁺Amersham CES3—2 mCi).

Capsaicin Antagonist Assay: E-19 DRG cells at 3 days in culture areincubated with serial concentrations of VR1 antagonists, in HBSS (Hanksbuffered saline solution supplemented with BSA 0.1 mg/mL and 1 mM Hepesat pH 7.4) for 15 min, room temperature. Cells are then challenged witha VR1 agonist, capsaicin (500 nM), in activation buffer containing 0.1mg/mL BSA, 15 mM Hepes, pH 7.4, and 10 μCi/mL ⁴⁵Ca²⁺ (Amersham CES3-2mCi) in Ham's F12 for 2 min at room temperature.

The following compounds exhibit IC50 values of less than 10 mM in theAcid Antagonist Assay:

-   (1H-benzoimidazol-4-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   (1H-benzotriazol-5-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   (1H-indazol-5-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   (1H-indol-4-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   (1H-indol-5-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   (1H-indol-6-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   (1H-indol-7-yl)-[6-(4-trifluoromethylphenyl]pyrimidin-4-yl)amine;-   (1-methyl-1H-benzoimidazol-4-yl)-[6-(4-trifluoromethyl)phenyl)pyrimidin-4-yl]amine;-   (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(6-phenylpyrimidin-4-yl)amine;-   (2,3-dihydrobenzo[1,4]dioxin-6-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   (2,3-dimethyl-1H-indol-7-yl)-[6-(4-(trifluoromethylphenyl)pyrimidin-4-yl]amine;-   (2-chloropyridin-3-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   (2-chloroquinolin-7-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   (2-chloroquinolin-8-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   (2-methoxyquinolin-7-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   (2-methyl-1H-benzoimidazol-4-yl)-[6-(4-trifluoromethyl)phenyl)pyrimidin-4-yl]-amine;-   (2-methylaminoquinolin-7-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine    dihydrochloride;-   (2-methylbenzothiazol-5-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   (2R)-{6-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]-2H¹³H-benzo[1,4]dioxin-2-yl}methanol;-   (3,4-dichlorophenyl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   (3,4-dimethylphenyl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   (3-chloro-2-methylphenyl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   (3H-benzotriazol-5-yl)-[6-(4-tert-butylphenyl)pyrimidin-4-yl]amine;-   (3-methanesulfonylphenyl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]    amine;-   (3-methylbenzo[d]isothiazol-5-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   (3-methylsulfanylphenyl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   (4-chloro-3-trifluoromethylphenyl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   (4-chlorophenyl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   (5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   (5-chloro-2-methylphenyl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   (6-methoxypyridin-3-yl)-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   [(2-morpholin-4-yl)quinolin-7-yl]-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine    hydrochloride;-   [2-amino-6-(4-tert-butylphenyl)pyrimidin-4-yl]-(2,3-dihydrobenzo[1,4]dioxin-6-yl)amine    hydrochloride;-   [5-(4-tert-butylphenyl)-6-phenyl-pyridazin-3-yl]-(1H-indol-5-yl)-amine;-   [5-(4-tert-butylphenyl)-6-phenylpyridazin-3-yl-(2,3-dihydrobenzo[1,4]dioxin-6-yl)amine;-   [6-(2-amino-4-trifluoromethylphenyl)pyrimidin-4-yl]benzothiazol-6-ylamine;-   [6-(4-tert-butylphenyl)-2-chloropyrimidin-4-yl]-(2,3-dihydrobenzo[1,4]dioxin-6-yl)amine;-   [6-(4-tert-butylphenyl)-2-methylpyrimidin-4-yl]-(2,3-dihydrobenzo[1,4]dioxin-6-yl)amine;-   [6-(4-tert-butylphenyl)pyrimidin-4-yl]-(1H-indol-4-yl)amine;-   [6-(4-tert-butylphenyl)pyrimidin-4-yl]-(1H-indol-5-yl)amine;-   [6-(4-tert-butylphenyl)pyrimidin-4-yl]-(1H-indol-6-yl)amine;-   [6-(4-tert-butylphenyl)pyrimidin-4-yl]-(2,3-dihydrobenzo[1,4]dioxin-6-yl)amine;-   [6-(4-tert-butylphenyl)pyrimidin-4-yl]-(3-methoxyphenyl)amine;-   [6-(4-tert-butylphenyl)pyrimidin-4-yl]naphthalen-1-ylamine;-   [6-(4-tert-butylphenyl)pyrimidin-4-yl]phenylamine;-   [6-(4-tert-butylphenylpyrimidin-4-yl]quinolin-3-ylamine;-   {1′-acetylspiro    [cyclopropane-1,3′-indolin-6′-yl]}-[6-(4-trifluoromethylphenyl)-pyrimidin-4-yl]amine;-   {7-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]-1H-indol-2-yl}    methanol;-   {spiro[cyclopropane-1,3′-indolin-6′-yl]}-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   1-{3,3-dimethyl-6-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]-2,3-dihydroindol-1-yl}ethanone;-   2-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]quinolin-8-ol;-   2-{5-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]pyridin-2-yloxy}    ethanol;-   3,4-dihydro-7-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]-1H-quinolin-2-one;-   4-methyl-7-{[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amino}    quinolin-2-ol, hydrochloride;-   6-[6-(4-tert-butylphenyl)pyrimidin-4-ylamino]-3,4-dihydro-2H-naphthalen-1-one;-   7-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]quinolin-2-ol;-   7-[6-(4-trifluoromethylphenyl]pyrimidin-4-ylamino]-1,3-dihydroindol-2-one;-   benzothiazol-5-yl-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl] amine;-   benzothiazol-6-yl-[5-(4-tert-butylphenyl)-6-phenylpyridazin-3-yl]    amine;-   benzothiazol-6-yl-[5,6-bis-(4-trifluoromethylphenyl)pyridazin-3-yl]amine;-   benzothiazol-6-yl-[6-(2-cyclohexylmethylamino-4-trifluoromethylphenyl)-pyrimidin-4-yl]    amine;-   benzothiazol-6-yl-[6-(2-naphthyl)-5-(4-trifluoromethylphenyl)pyridazin-3-yl]amine;-   benzothiazol-6-yl-[6-(4-fluorophenyl)-5-(4-trifluoromethylphenyl)pyridazin-3-yl]amine;-   benzothiazol-6-yl-[6-(4-tert-butylphenyl)pyrimidin-4-yl]amine;-   benzothiazol-6-yl-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   benzothiazol-6-yl-[6-chloro-5-(4-trifluoromethylphenyl)pyridazin-3-yl]amine;-   benzothiazol-6-yl-[6-phenyl-5-(4-trifluoromethylphenyl)pyridazin-3-yl]amine;-   benzothiazol-6-yl-[6-pyridin-3-yl-5-(4-trifluoromethylphenyl)pyridazin-3-yl]amine;-   benzothiazol-6-yl-[6-pyridin-4-yl-5-(4-trifluoromethylphenyl)pyridazin-3-yl]amine;-   N-{4-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]-1H-benzoimidazol-2-yl}acetamide;-   N-{4-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]benzothiazol-2-yl}acetamide;-   N-{4-[6-(4-trifluoromethylphenyl)pyrimidin-4-ylamino]phenyl}    acetamide;-   N⁴-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]-1H-benzoimidazole-2,4-diamine;-   N⁴-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]benzothiazole-2,4-diamine;-   N⁴-benzothiazol-6-yl-6-(4-tert-butylphenyl)pyrimidine-2,4-diamine    hydrochloride;-   N⁷-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]quinoline-2,7-diamine;-   N⁸-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]quinoline-2,8-diamine;-   naphthalen-1-yl-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   naphthalen-2-yl-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl] amine;-   o-tolyl-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   phenyl-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl] amine;-   p-tolyl-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl] amine;-   quinolin-3-yl-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   5 quinolin-5-yl-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   quinolin-6-yl-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine;-   quinolin-8-yl-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl]amine; and-   quinolyl-7-yl-[6-(4-trifluoromethylphenyl)pyrimidin-4-yl] amine.

Acid Antagonist Assay: Compounds are pre-incubated with E-19 DRG cellsat room temperature for 2 minutes prior to addition of ⁴⁵Ca²⁺ in 30 mMHepes/Mes buffer (Final Assay pH 5) and then left for an additional 2minutes prior to compound washout. Final concentration of ⁴⁵Ca²⁺(Amersham CES3-2 mCi) is 10 μCi/mL.

Agonist Assay: Compounds are incubated with E-19 DRG cells at roomtemperature for 2 minutes in the presence of ⁴⁵Ca²⁺ prior to compoundwashout. Final ⁴⁵Ca²⁺ (Amersham CES3—2 mCi) at 10 μCi/mL.

Compound Washout and Analysis: Assay plates are washed using an ELX405plate washer (Bio-Tek Instruments Inc.) immediately after functionalassay. Wash 3× with PBS, 0.1 mg/nL BSA. Aspirate between washes. Readplates using a MicroBeta Jet (Wallac Inc.). Compound activity is thencalculated using appropriate computational algorithms.

⁴⁵Calcium²⁺ Assay Protocol

Compounds may be assayed using Chinese Hamster Ovary cell lines stablyexpressing either human VR1 or rat VR1 under a CMV promoter. Cells couldbe cultured in a Growth Medium, routinely passaged at 70% confluencyusing trypsin and plated in an assay plate 24 hours prior to compoundevaluation.

Possible Growth Medium:

-   -   DMEM, high glucose (Gibco 11965-084).    -   10% Dialyzed serum (Hyclone SH30079.03).    -   1× Non-Essential Amino Acids (Gibco 11140-050).    -   1× Glutamine-Pen-Strep (Gibco 10378-016).    -   Geneticin, 450 μg/mL (Gibco 10131-035).

Compounds could be diluted in 100% DMSO and tested for activity overseveral log units of concentration [40 μM-2 pM]. Compounds may befurther diluted in HBSS buffer (pH 7.4) 0.1 mg/mL BSA, prior toevaluation. Final DMSO concentration in assay would be 0.5-1%. Eachassay plate could be controlled with a buffer only and a knownantagonist compound (either capsazepine or one of the described VR1antagonists).

Activation of VR1 could be achieved in these cellular assays usingeither a capsaicin stimulus (ranging from 0.1-1 μM) or by an acidstimulus (addition of 30 mM Hepes/Mes buffered at pH 4.1). Compoundscould also be tested in an assay format to evaluate their agonistproperties at VR1.

Capsaicin Antagonist Assay: Compounds may be pre-incubated with cells(expressing either human or rat VR1) at room temperature for 2 minutesprior to addition of ⁴⁵Ca²⁺ and Capsaicin and then left for anadditional 2 minutes prior to compound washout. Capsaicin (200 nM) canbe added in HAM's F12, 0.1 mg/mL BSA, 15 mM Hepes at pH 7.4. Final⁴⁵Ca²⁺ (Amersham CES3—2 mCi) added could be 10 μCi/mL.

Acid Antagonist Assay: Compounds can be pre-incubated with cells(expressing either human or rat VR1) for 2 minutes prior to addition of⁴⁵Ca²⁺ in 30 mM Hepes/Mes buffer (Final Assay pH 5) and then left for anadditional 2 minutes prior to compound washout. Final ⁴⁵Ca²⁺ (AmershamCES3—2 mCi) added could be 10 μCi/mL.

Agonist Assay: Compounds can be incubated with cells (expressing eitherhuman or rat VR1) for 2 minutes in the presence of ⁴⁵Ca²⁺ prior tocompound washout. Final ⁴⁵Ca²⁺ (Amersham CES3—2 mCi) added could be 10μCi/mL.

Compound Washout and Analysis: Assay plates would be washed using anELX405 plate washer (Bio-Tek Instruments Inc.) immediately after thefunctional assay. One could wash 3× with PBS, 0.1 mg/mL BSA, aspiratingbetween washes. Plates could then be read using a MicroBeta Jet (WallacInc.) and compound activity calculated using appropriate computationalalgorithms.

Useful nucleic acid sequences and proteins may be found in U.S. Pat.Nos. 6,335,180, 6, 406,908 and 6,239,267, herein incorporated byreference in their entirety.

For the treatment of vanilloid-receptor-diseases, such as acute,inflammatory and neuropathic pain, dental pain, general headache,migraine, cluster headache, mixed-vascular and non-vascular syndromes,tension headache, general inflammation, arthritis, rheumatic diseases,osteoarthritis, inflammatory bowel disorders, inflammatory eyedisorders, inflammatory or unstable bladder disorders, psoriasis, skincomplaints with inflammatory components, chronic inflammatoryconditions, inflammatory pain and associated hyperalgesia and allodynia,neuropathic pain and associated hyperalgesia and allodynia, diabeticneuropathy pain, causalgia, sympathetically maintained pain,deafferentation syndromes, asthma, epithelial tissue damage ordysfunction, herpes simplex, disturbances of visceral motility atrespiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritis, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders, the compounds of the present invention may be administeredorally, parentally, by inhalation spray, rectally, or topically indosage unit formulations containing conventional pharmaceuticallyacceptable carriers, adjuvants, and vehicles. The term parenteral asused herein includes, subcutaneous, intravenous, intramuscular,intrastemal, infusion techniques or intraperitoneally.

Treatment of diseases and disorders herein is intended to also includethe prophylactic administration of a compound of the invention, apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman) believed to be in need of preventative treatment, such as, forexample, pain, inflammation and the like.

The dosage regimen for treating vanilloid-receptor-mediated diseases,cancer, and/or hyperglycemia with the compounds of this invention and/orcompositions of this invention is based on a variety of factors,including the type of disease, the age, weight, sex, medical conditionof the patient, the severity of the condition, the route ofadministration, and the particular compound employed. Thus, the dosageregimen may vary widely, but can be determined routinely using standardmethods. Dosage levels of the order from about 0.01 mg to 30 mg perkilogram of body weight per day, preferably from about 0.1 mg to 10mg/kg, more preferably from about 0.25 mg to 1 mg/kg are useful for allmethods of use disclosed herein.

The pharmaceutically active compounds of this invention can be processedin accordance with conventional methods of pharmacy to produce medicinalagents for administration to patients, including humans and othermammals.

For oral administration, the pharmaceutical composition may be in theform of, for example, a capsule, a tablet, a suspension, or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a given amount of the active ingredient. For example,these may contain an amount of active ingredient from about 1 to 2000mg, preferably from about 1 to 500 mg, more preferably from about 5 to150 mg. A suitable daily dose for a human or other mammal may varywidely depending on the condition of the patient and other factors, but,once again, can be determined using routine methods.

The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water.The daily parenteral dosage regimen will be from about 0.1 to about 30mg/kg of total body weight, preferably from about 0.1 to about 10 mg/kg,and more preferably from about 0.25 mg to 1 mg/kg.

Injectable preparations, such as sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known areusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable non-irritating excipient such as cocoabutter and polyethylene glycols that are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

A suitable topical dose of active ingredient of a compound of theinvention is 0.1 mg to 150 mg administered one to four, preferably oneor two times daily. For topical administration, the active ingredientmay comprise from 0.001% to 10% w/w, e.g, from 1% to 2% by weight of theformulation, although it may comprise as much as 10% w/w, but preferablynot more than 5% w/w, and more preferably from 0.1% to 1% of theformulation.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin(e.g., liniments, lotions, ointments, creams, or pastes) and dropssuitable for administration to the eye, ear, or nose.

For administration, the compounds of this invention are ordinarilycombined with one or more adjuvants appropriate for the indicated routeof administration. The compounds may be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, stearic acid, talc,magnesium stearate, magnesium oxide, sodium and calcium salts ofphosphoric and sulfuric acids, acacia, gelatin, sodium alginate,polyvinyl-pyrrolidine, and/or polyvinyl alcohol, and tableted orencapsulated for conventional administration. Alternatively, thecompounds of this invention may be dissolved in saline, water,polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil,cottonseed oil, sesame oil, tragacanth gum, and/or various buffers.Other adjuvants and modes of administration are well known in thepharmaceutical art. The carrier or diluent may include time delaymaterial, such as glyceryl monostearate or glyceryl distearate alone orwith a wax, or other materials well known in the art.

The pharmaceutical compositions may be made up in a solid form(including granules, powders or suppositories) or in a liquid form(e.g., solutions, suspensions, or emulsions). The pharmaceuticalcompositions may be subjected to conventional pharmaceutical operationssuch as sterilization and/or may contain conventional adjuvants, such aspreservatives, stabilizers, wetting agents, emulsifiers, buffers etc.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose, lactose, or starch. Such dosage forms may also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting, sweetening,flavoring, and perfuming agents.

Compounds of the present invention can possess one or more asymmetriccarbon atoms and are thus capable of existing in the form of opticalisomers as well as in the form of racemic or non-racemic mixturesthereof. The optical isomers can be obtained by resolution of theracemic mixtures according to conventional processes, e.g., by formationof diastereoisomeric salts, by treatment with an optically active acidor base. Examples of appropriate acids are tartaric, diacetyltartaric,dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and thenseparation of the mixture of diastereoisomers by crystallizationfollowed by liberation of the optically active bases from these salts. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column optimally chosen to maximize theseparation of the enantiomers. Still another available method involvessynthesis of covalent diastereoisomeric molecules by reacting compoundsof the invention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of theinvention can likewise be obtained by using active starting materials.These isomers may be in the form of a free acid, a free base, an esteror a salt.

Likewise, the compounds of this invention may exist as isomers, that iscompounds of the same molecular formula but in which the atoms, relativeto one another, are arranged differently. In particular, the alkylenesubstituents of the compounds of this invention, are normally andpreferably arranged and inserted into the molecules as indicated in thedefinitions for each of these groups, being read from left to right.However, in certain cases, one skilled in the art will appreciate thatit is possible to prepare compounds of this invention in which thesesubstituents are reversed in orientation relative to the other atoms inthe molecule. That is, the substituent to be inserted may be the same asthat noted above except that it is inserted into the molecule in thereverse orientation. One skilled in the art will appreciate that theseisomeric forms of the compounds of this invention are to be construed asencompassed within the scope of the present invention.

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. The salts include, but are notlimited to, the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methansulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 2-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate, andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids that may be employed to from pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulfuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Otherexamples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases.

Also encompassed in the scope of the present invention arepharmaceutically acceptable esters of a carboxylic acid or hydroxylcontaining group, including a metabolically labile ester or a prodrugform of a compound of this invention. A metabolically labile ester isone which may produce, for example, an increase in blood levels andprolong the efficacy of the corresponding non-esterified form of thecompound. A prodrug form is one which is not in an active form of themolecule as administered but which becomes therapeutically active aftersome in vivo activity or biotransformation, such as metabolism, forexample, enzymatic or hydrolytic cleavage. For a general discussion ofprodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examplesof a masked carboxylate anion include a variety of esters, such as alkyl(for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl),aralkyl (for example, benzyl, p-methoxybenzyl), andalkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have beenmasked as arylcarbonyloxymethyl substituted derivatives which arecleaved by esterases in vivo releasing the free drug and formaldehyde(Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidicNH group, such as imidazole, imide, indole and the like, have beenmasked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs,Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.EP 039,051 (Sloan and Little, Apr. 11, 1981) discloses Mannich-basehydroxamic acid prodrugs, their preparation and use. Esters of acompound of this invention, may include, for example, the methyl, ethyl,propyl, and butyl esters, as well as other suitable esters formedbetween an acidic moiety and a hydroxyl containing moiety. Metabolicallylabile esters, may include, for example, methoxymethyl, ethoxymethyl,iso-propoxymethyl, α-methoxyethyl, groups such asα-((C₁-C₄)alkyloxy)ethyl, for example, methoxyethyl, ethoxyethyl,propoxyethyl, iso-propoxyethyl, etc.; 2-oxo-1,3-dioxolen-4-ylmethylgroups, such as 5-methyl-2-oxo-1,3,dioxolen-4-ylmethyl, etc.; C₁-C₃alkylthiomethyl groups, for example, methylthiomethyl, ethylthiomethyl,isopropylthiomethyl, etc.; acyloxymethyl groups, for example,pivaloyloxymethyl, α-acetoxymethyl, etc.; ethoxycarbonyl-1-methyl; orα-acyloxy-α-substituted methyl groups, for example α-acetoxyethyl.

Further, the compounds of the invention may exist as crystalline solidswhich can be crystallized from common solvents such as ethanol,N,N-dimethyl-formamide, water, or the like. Thus, crystalline forms ofthe compounds of the invention may exist as polymorphs, solvates and/orhydrates of the parent compounds or their pharmaceutically acceptablesalts. All of such forms likewise are to be construed as falling withinthe scope of the invention.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more compounds of the invention or other agents. Whenadministered as a combination, the therapeutic agents can be formulatedas separate compositions that are given at the same time or differenttimes, or the therapeutic agents can be given as a single composition.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. A compound having the structure:

or any pharmaceutically-acceptable salt thereof, wherein: n isindependently, at each instance, 0, 1 or
 2. R¹ is

 or R¹ is a naphthyl substituted by 0, 1, 2 or 3 substituentsindependently selected from R⁵; or R¹ is R^(b) substituted by 1, 2 or 3substituents independently selected from R⁵; R² is, independently, ineach instance, R¹⁰, C₁₋₈alkyl substituted by 0, 1 or 2 substituentsselected from R¹⁰, —(CH₂)_(n)phenyl substituted by 0, 1, 2 or 3substituents independently selected from R¹⁰, or a saturated orunsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3heteroatoms independently selected from N, O and S, wherein no more than2 of the ring members are O or S, wherein the heterocycle is optionallyfused with a phenyl ring, and the heterocycle or fused phenyl ring issubstituted by 0, 1, 2 or 3 substituents independently selected fromR¹⁰; R³ is, independently, in each instance, H, halo, —NHC₁₋₃alkyl,—N(C₁₋₃alkyl)C₁₋₃alkyl, or C₁₋₃alkyl; wherein, at least one of R² and R³is other than H; R⁴ is

 or  R⁴ is a saturated or unsaturated 5- or 6-membered ring heterocyclecontaining 1, 2 or 3 atoms selected from O, N and S that is optionallyvicinally fused with a saturated or unsaturated 3- or 4-atom bridgecontaining 0, 1, 2 or 3 atoms selected from O, N and S with theremaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2, wherein the carbon atoms of the heterocycleand bridge are substituted by 0, 1, 2 or 3 substituents independentlyselected from R^(e), C₁₋₄haloalkyl, halo, nitro, cyano, oxo, —OR^(f),—S(═O)_(n)R^(e), —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(f),—C(═O)NR^(a)R^(f) and, —OC₁₋₆alkylC(═O)OR^(e), —NR^(a)R^(f),—NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆ alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(e), —C(═O)OR^(e), —OC(═O)R^(e),—C(═O)NR^(a)R^(f) and —NR^(a)C(═O)R^(e); and unsaturated carbon atomsmay be additionally substituted by ═O; and any available nitrogen atomsin the heterocycle and bridge are substituted by H, —C₁₋₆alkylOR^(f),R^(e), —C₁₋₆alkylNR^(a)R^(f), —C₁₋₃alkylC(═O)OR^(e),—C₁₋₃alkylC(═O)NR^(a)R^(f), —C₁₋₃alkylOC(═O)R^(e),—C₁₋₃alkylNR^(a)C(═O)R^(e), —C(═O)R^(c) or —C₁₋₃alkylR^(c); or R⁴ isnaphthyl substituted by 1, 2 or 3 substituents independently selectedfrom C₁₋₄haloalkyl, halo, nitro, cyano, —S(═O)_(n)R^(e),—OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—OC₁₋₆alkylC(═O)OR^(c), —NR^(a)C₁₋₄haloalkyl,—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(e),—C(═O)OR^(c), —OC(═O)R^(e) and —C(═O)NR^(a)R^(f); but in no instance isR⁴ 3,5-ditrifluoromethylphenyl, 3-trifluoromethyl-4-fluorophenyl,-phenyl-(C₁₋₈alkyl), -phenyl-O—(C₁₋₆alkyl), -phenyl-NR^(a)R^(a) or-phenyl-N(R^(a))C(═O)(C₁₋₈alkyl); R⁵ is independently, at each instance,R^(f), R^(g), halo, nitro, cyano, —OR^(e), —OR^(g),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e),—OC(═O)NR^(a)R^(f), a phenyl ring substituted with 0, 1, 2, or 3substituents independently selected from R¹⁰; or R⁵ is a saturated orunsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atomsselected from O, N and S, substituted with 0, 1, 2, or 3 substituentsindependently selected from R¹⁰; R⁶ is independently, at each instance,H, C₁₋₅alkyl, C₁₋₄haloalkyl, halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a) or—NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a),—S(C₁₋₆alkyl), a phenyl ring substituted with 1, 2, or 3 substituentsindependently selected from R¹⁰; or R⁶ is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected fromO, N and S substituted with 0, 1, 2, or 3 substituents independentlyselected from R¹⁰; R⁷ is independently, at each instance, H,acyclicC₁₋₈alkyl, C₁₋₄haloalkyl, halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a) or—S(C₁₋₆alkyl); or R⁷ is a saturated or unsaturated 4- or 5-membered ringheterocycle containing a single nitrogen atom, wherein the ring issubstituted with 0, 1 or 2 substituents independently selected fromhalo, C₁₋₂haloalkyl and C₁₋₃alkyl; R⁸ is independently, at eachinstance, H, C₁₋₅alkyl, C₁₋₄haloalkyl, halo, —OC₁₋₆alkyl,—OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—NR^(a)R^(a), —NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a),—S(C₁₋₆alkyl), a phenyl ring substituted with 1, 2, or 3 substituentsindependently selected from R¹⁰, or R⁸ is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected fromO, N and S substituted with 0, 1, 2, or 3 substituents independentlyselected from R¹⁰; R⁹ is independently, at each instance, R^(f), R^(g),halo, nitro, cyano, —OR^(e), —OR^(g), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g), —NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl, —CO₂R^(e),—C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g), —NR^(f)C(═O)R^(e),—NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f), —NR^(f)CO₂R^(e),—C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e),—S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e), —OC(═O)NR^(a)R^(f), a phenylring substituted with 0, 1, 2, or 3 substituents independently selectedfrom R¹⁰; or R⁹ is a saturated or unsaturated 5- or 6-membered ringheterocycle containing 1, 2 or 3 atoms selected from O, N and Ssubstituted with 0, 1, 2, or 3 substituents independently selected fromR¹⁰; or R⁹ is a saturated or unsaturated 4- or 5-membered ringheterocycle containing a single nitrogen atom, wherein the ring issubstituted with 0, 1 or 2 substituents independently selected fromhalo, C₁₋₂haloalkyl and C₁₋₃alkyl; wherein at least one of R⁵, R⁶, R⁷,R⁸ and R⁹ is C₁₋₈alkyl, C₁₋₄haloalkyl, halo, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)C₁₋₄haloalkyl,—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a),—C₁₋₆alkylNR^(a)R^(a) or —S(C₁₋₆alkyl); R¹⁰ is independently, at eachinstance, selected from H, C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro,—C(═O)(C₁₋₈alkyl), —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkyNR^(a)R^(a), —OC₂alkylOR^(a), SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl) —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁰ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁰ is C₁₋₄alkylsubstituted by 0, 1, 2 or 3 groups selected from C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)(C₁₋₈alkyl), —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),NR^(a)R^(a), N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); R¹¹ is independently,at each instance, selected from H, C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)(C₁₋₈alkyl), —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a) or R¹¹ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),NR^(a)R^(a), N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹¹ isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁰ and R¹¹together are a saturated or unsaturated 3- or 4-atom bridge containing1, 2 or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the bridge is substituted by 0, 1 or 2 substituents selectedfrom ═O, R^(e), halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(e),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(f))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(f), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(f))C(═O)R^(e),—S(═O)₂N(R^(f))C(═O)OR^(e), —S(═O)₂N(R^(f))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(f))C(═O)R^(e), —N(R^(f))C(═O)OR^(e),—N(R^(f))C(═O)NR^(a)R^(f), —N(R^(f))C(═NR^(a))NR^(a)R^(f),—N(R^(f))S(═O)₂R^(e), —N(R^(f))S(═O)₂NR^(a)R^(f),—NR^(f)C₂₋₆alkylNR^(a)R^(f) and —NR^(f)C₂₋₆alkylOR^(f); R¹² isindependently, at each instance, selected from H, C₁₋₈alkyl,—C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkyNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₁-alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl) —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C g-8alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹² is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl) —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹² isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl) —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); wherein if R¹¹or R¹³ is CF₃, then R¹² is not F; or R¹¹ and R¹² together are asaturated or unsaturated 3- or 4-atom bridge containing 1, 2 or 3 atomsselected from O, N and S with the remaining atoms being carbon, so longas the combination of O and S atoms is not greater than 2, wherein thebridge is substituted by 0, 1 or 2 substituents selected from ═O, R^(e),halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(e), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(f))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(f), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(f))C(═O)R^(e), —S(═O)₂N(R^(f))C(═O)OR^(e),—S(═O)₂N(R^(f))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(f))C(═O)R^(e),—N(R^(f))C(═O)OR^(e), —N(R^(f))C(═O)NR^(a)R^(f),—N(R^(f))C(═NR^(a))NR^(a)R^(f), —N(R^(f))S(═O)₂R^(e),—N(R^(f))S(═O)₂NR^(a)R^(f), —NR^(f)C₂₋₆alkylNR^(a)R^(f) and—NR^(f)C₂₋₆alkylOR^(f); wherein when R³ is NH₂, then -R¹¹-R¹²- is not—C═C—C═N— or any substituted version thereof; R¹³ is independently, ateach instance, selected from H, C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano,nitro, —C(═O)(C₁₋₈alkyl), —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a),N(R^(a))C(═NR^(a))NR^(a)R^(a)—N(R^(a))S(═O)₂(C₁₋₈alkyl),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and—NR^(a)C₂₋₆alkylOR^(a); or R¹³ is a saturated or unsaturated 5-, 6- or7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclicring containing 1, 2 or 3 atoms selected from N, O and S, wherein thering is fused with 0 or 1 benzo groups and 0 or 1 saturated orunsaturated 5-, 6- or 7-membered heterocyclic ring containing 1, 2 or 3atoms selected from N, O and S; wherein the carbon atoms of the ring aresubstituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by0, 1, 2 or 3 groups selected from C₁₋₈alkyl, C₁₋₄-haloalkyl, halo,cyano, nitro, —C(═O)(C₁₋₈alkyl), —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹³ isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); R¹⁴ isindependently, at each instance, selected from H, C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁴ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁴ isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl), —C(═O)O(C18alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); wherein at leastone of R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ is other than H; R^(a) isindependently, at each instance, H, phenyl, benzyl or C₁₋₆alkyl; R^(b)is a heterocycle selected from the group of thiophene, pyrrole,1,3-oxazole, 1,3-thiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole,1,2,3-oxadiazole, 1,2,3-thiadiazole, 1H-1,2,3-triazole, isothiazole,1,2,4-oxadiazole, 1,2,4-thiadiazole, 1,2,3,4-oxatriazole,1,2,3,4-thiatriazole, 1H-1,2,3,4-tetraazole, 1,2,3,5-oxatriazole,1,2,3,5-thiatriazole, furan, imidazol-1-yl, imidazol-4-yl,1,2,4-triazol-4-yl, 1,2,4-triazol-5-yl, isoxazol-3-yl, isoxazol-5-yl,pyrazol-3-yl, pyrazol-5-yl, thiolane, pyrrolidine, tetrahydrofuran,4,5-dihydrothiophene, 2-pyrroline, 4,5-dihydrofuran, pyridazine,pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,2,4-triazine,1,3,5-triazine, pyridine, 2H-3,4,5,6-tetrahydropyran, thiane,1,2-diazaperhydroine, 1,3-diazaperhydroine, piperazine,1,3-oxazaperhydroine, morpholine, 1,3-thiazaperhydroine,1,4-thiazaperhydroine, piperidine, 2H-3,4-dihydropyran,2,3-dihydro-4H-thiin, 1,4,5,6-tetrahydropyridine, 2H-5,6-dihydropyran,2,3-dihydro-6H-thiin, 1,2,5,6-tetrahydropyridine,3,4,5,6-tetrahydropyridine, 4H-pyran, 4H-thiin, 1,4-dihydropyridine,1,4-dithiane, 1,4-dioxane, 1,4-oxathiane, 1,2-oxazolidine,1,2-thiazolidine, pyrazolidine, 1,3-oxazolidine, 1,3-thiazolidine,imidazolidine, 1,2,4-oxadiazolidine, 1,3,4-oxadiazolidine,1,2,4-thiadiazolidine, 1,3,4-thiadiazolidine, 1,2,4-triazolidine,2-imidazoline, 3-imidazoline, 2-pyrazoline, 4-imidazoline,2,3-dihydroisothiazole, 4,5-dihydroisoxazole, 4,5-dihydroisothiazole,2,5-dihydroisoxazole, 2,5-dihydroisothiazole, 2,3-dihydroisoxazole,4,5-dihydrooxazole, 2,3-dihydrooxazole, 2,5-dihydrooxazole,4,5-dihydrothiazole, 2,3-dihydrothiazole, 2,5-dihydrothiazole,1,3,4-oxathiazolidine, 1,4,2-oxathiazolidine,2,3-dihydro-1H-[1,2,3]triazole, 2,5-dihydro-1H-[1,2,3]triazole,4,5-dihydro-1H-[1,2,3]triazole, 2,3-dihydro-1H-[1,2,4]triazole,4,5-dihydro-1H-[1,2,4]triazole, 2,3-dihydro-[1,2,4]oxadiazole,2,5-dihydro-[1,2,4]oxadiazole, 4,5-dihydro-[1,2,4]thiadiazole,2,3-dihydro-[1,2,4] thidiazole, 2,5-dihydro-[1,2,4] thiadiazole,4,5-dihydro-[1,2,4] thiadiazole, 2,5-dihydro-[1,2,4]oxadiazole,2,3-dihydro-[1,2,4]oxadiazole, 4,5-dihydro-[1,2,4]oxadiazole,2,5-dihydro-[1,2,4]thiadiazole, 2,3-dihydro-[1,2,4] thiadiazole,4,5-dihydro-[1,2,4] thiadiazole, 2,3-dihydro-[1,3,4]oxadiazole,2,3-dihydro-[1,3,4]thiadiazole, [1,4,2]oxathiazole, [1,3,4]oxathiazole,1,3,5-triazaperhydroine, 1,2,4-triazaperhydroine,1,4,2-dithiazaperhydroine, 1,4,2-dioxazaperhydroine,1,3,5-oxadiazaperhydroine, 1,2,5-oxadiazaperhydroine,1,3,4-thiadiazaperhydroine, 1,3,5-thiadiazaperhydroine,1,2,5-thiadiazaperhydroine, 1,3,4-oxadiazaperhydroine,1,4,3-oxathiazaperhydroine, 1,4,2-oxathiazaperhydroine,1,4,5,6-tetrahydropyridazine, 1,2,3,4-tetrahydropyridazine,1,2,3,6-tetrahydropyridazine, 1,2,5,6-tetrahydropyrimidine,1,2,3,4-tetrahydropyrimidine, 1,4,5,6-tetrahydropyrimidine,1,2,3,6-tetrahydropyrazine, 1,2,3,4-tetrahydropyrazine,5,6-dihydro-4H-[1,2]oxazine, 5,6-dihydro-2H-[1,2]oxazine,3,6-dihydro-2H-[1,2]oxazine, 3,4-dihydro-2H-[1,2]oxazine,5,6-dihydro-4H-[1,2]thiazine, 5,6-dihydro-2H-[1,2] thiazine,3,6-dihydro-2H-[1,2] thiazine, 3,4-dihydro-2H-[1,2] thiazine,5,6-dihydro-2H-[1,3]oxazine, 5,6-dihydro-4H-[1,3]oxazine,3,6-dihydro-2H-[1,3]oxazine, 3,4-dihydro-2H-[1,3]oxazine,3,6-dihydro-2H-[1,4]oxazine, 3,4-dihydro-2H-[1,4]oxazine,5,6-dihydro-2H-[1,3]thiazine, 5,6-dihydro-4H-[1,3]thiazine,3,6-dihydro-2H-[1,3]thiazine, 3,4-dihydro-2H-[1,3]thiazine,3,6-dihydro-2H-[1,4]thiazine, 3,4-dihydro-2H-[1,4]thiazine,1,2,3,6-tetrahydro-[1,2,4]triazine, 1,2,3,4-tetrahydro-[1,2,4]triazine,1,2,3,4-tetrahydro-[1,3,5]triazine, 2,3,4,5-tetrahydro-[1,2,4]triazine,1,4,5,6-tetrahydro-[1,2,4]triazine, 5,6-dihydro-[1,4,2]dioxazine,5,6-dihydro-[1,4,2]dioxazine, 5,6-dihydro-[1,4,2]dithiazine,2,3-dihydro-[1,4,2]dioxazine, 3,4-dihydro-2H-[1,3,4]oxadiazine,3,6-dihydro-2H-[1,3,4]oxadiazine, 3,4-dihydro-2H-[1,3,5]oxadiazine,3,6-dihydro-2H-[1,3,5]oxadiazine, 5,6-dihydro-2H-[1,2,5]oxadiazine,5,6-dihydro-4H-[1,2,5]oxadiazine, 3,4-dihydro-2H-[1,3,4]thiadiazine,3,6-dihydro-2H-[1,3,4]thiadiazine, 3,4-dihydro-2H-[1,3,5]thiadiazine,3,6-dihydro-2H-[1,3,5]thiadiazine, 5,6-dihydro-2H-[1,2,5]thiadiazine,5,6-dihydro-4H-[1,2,5]thiadiazine, 5,6-dihydro-2H-[1,2,3]oxadiazine,3,6-dihydro-2H-[1,2,5]oxadiazine, 5,6-dihydro-4H-[1,3,4]oxadiazine,3,4-dihydro-2H-[1,2,5]oxadiazine, 5,6-dihydro-2H-[1,2,3]thiadiazine,3,6-dihydro-2H-[1,2,5]thiadiazine, 5,6-dihydro-4H-[1,3,4]thiadiazine,3,4-dihydro-2H-[1,2,5]thiadiazine, 5,6-dihydro-[1,4,3]oxathiazine,5,6-dihydro-[1,4,2]oxathiazine, 2,3-dihydro-[1,4,3]oxathiazine,2,3-dihydro-[1,4,2]oxathiazine, 4,5-dihydropyridine,1,6-dihydropyridine, 5,6-dihydropyridine, 2H-pyran, 2H-thiin,3,6-dihydropyridine, 2,3-dihydropyridazine, 2,5-dihydropyridazine,4,5-dihydropyridazine, 1,2-dihydropyridazine, 2,3-dihydropyrimidine,2,5-dihydropyrimidine, 5,6-dihydropyrimidine, 3,6-dihydropyrimidine,4,5-dihydropyrazine, 5,6-dihydropyrazine, 3,6-dihydropyrazine,4,5-dihydropyrazine, 1,4-dihydropyrazine, 1,4-dithiin, 1,4-dioxin,2H-1,2-oxazine, 6H-1,2-oxazine, 4H-1,2-oxazine, 2H-1,3-oxazine,4H-1,3-oxazine, 6H-1,3-oxazine, 2H-1,4-oxazine, 4H-1,4-oxazine,2H-1,3-thiazine, 2H-1,4-thiazine, 4H-1,2-thiazine, 6H-1,3-thiazine,4H-1,4-thiazine, 2H-1,2-thiazine, 6H-1,2-thiazine, 1,4-oxathiin,2H,5H-1,2,3-triazine, 1H,4H-1,2,3-triazine, 4,5-dihydro-1,2,3-triazine,1H,6H-1,2,3-triazine, 1,2-dihydro-1,2,3-triazine,2,3-dihydro-1,2,4-triazine, 3H,6H-1,2,4-triazine, 1H,6H-1,2,4-triazine,3,4-dihydro-1,2,4-triazine, 1H,4H-1,2,4-triazine,5,6-dihydro-1,2,4-triazine, 4,5-dihydro-1,2,4-triazine,2H,5H-1,2,4-triazine, 1,2-dihydro-1,2,4-triazine, 1H,4H-1,3,5-triazine,1,2-dihydro-1,3,5-triazine, 1,4,2-dithiazine, 1,4,2-dioxazine,2H-1,3,4-oxadiazine, 2H-1,3,5-oxadiazine, 6H-1,2,5-oxadiazine,4H-1,3,4-oxadiazine, 4H-1,3,5-oxadiazine, 4H-1,2,5-oxadiazine,2H-1,3,5-thiadiazine, 6H-1,2,5-thiadiazine, 4H-1,3,4-thiadiazine,4H-1,3,5-thiadiazine, 4H-1,2,5-thiadiazine, 2H-1,3,4-thiadiazine,6H-1,3,4-thiadiazine, 6H-1,3,4-oxadiazine and 1,4,2-oxathiazine, whereinthe heterocycle is optionally vicinally fused with a saturated orunsaturated 5-, 6- or 7-membered ring containing 0, 1 or 2 atomsindependently selected from N, O and S; R^(c) is independently, in eachinstance, phenyl substituted by 0, 1 or 2 groups selected from halo,C₁₋₄alkyl, C₁₋₃haloalkyl, —OR^(a) and —NR^(a)R^(a); or R^(c) is asaturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein nomore than 2 of the ring members are O or S, wherein the heterocycle isoptionally fused with a phenyl ring, and the carbon atoms of theheterocycle are substituted by 0, 1 or 2 oxo groups, wherein theheterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OR^(a) and—NR^(a)R^(a); R^(d) is hydrogen or —CH₃; R^(e) is, independently, ineach instance, C₁₋₈alkyl substituted by 0, 1, 2, 3 or 4 substituentsselected from halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), OR^(a), —OC(═O)R^(a),OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); and wherein theC₁₋₈alkyl is additionally substituted by 0 or 1 groups independentlyselected from R^(g); R^(f) is, independently, in each instance, R^(e) orH; and R^(g) is, independently, in each instance, a saturated orunsaturated 5- or 6-membered monocyclic ring containing 1, 2 or 3 atomsselected from N, O and S, so long as the combination of O and S atoms isnot greater than 2, wherein the carbon atoms of the ring are substitutedby 0 or 1 oxo groups.
 2. A compound according to claim 1, wherein: R¹ is

R⁴ is

 or  R⁴ is a saturated or unsaturated 5- or 6-membered ring heterocyclecontaining 1, 2 or 3 atoms selected from O, N and S that is vicinallyfused with a saturated or unsaturated 3- or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the carbon atoms of the heterocycle and bridge aresubstituted by 0, 1, 2 or 3 substituents independently selected fromR^(e), C₁₋₄haloalkyl, halo, nitro, cyano, oxo, —OR^(f), —S(═O)_(n)R^(e),—OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—OC₁₋₆alkylC(═O)OR^(e), —NR^(a)R^(f), —NR^(a)C₁₋₄haloalkyl,—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(e),—C(═O)OR^(e), —OC(═O)R^(e), —C(═O)NR^(a)R^(f) and —NR^(a)C(═O)R^(e); andunsaturated carbon atoms may be additionally substituted by ═O; and anyavailable nitrogen atoms in the heterocycle and bridge are substitutedby H, —C₁₋₆alkylOR^(f), R^(e), —C₁₋₆alkylNR^(a)R^(f),—C₁₋₃alkylC(═O)OR^(e), —C₁₋₃alkylC(═O)NR^(a)R^(f),—C₁₋₃alkylOC(═O)R^(e), —C₁₋₃alkylNR^(a)C(═O)R^(e), —C(═O)R^(c) or—C₁₋₃alkylR^(c); R⁷ is independently, at each instance, C₃₋₅alkyl orC₁₋₂haloalkyl; and R¹⁰ and R¹¹ together are a saturated or unsaturated3-atom bridge containing 1, 2 or 3 atoms selected from O, N and S withthe remaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2, wherein the bridge is substituted by 0, 1or 2 substituents selected from ═O, R^(e), halo, cyano, nitro,—C(═O)R^(e), —C(═O)OR^(e), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f),—OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(f))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(f), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(f))C(═O)R^(e),—S(═O)₂N(R^(f))C(═O)OR^(e), —S(═O)₂N(R^(f))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(f))C(═O)R^(e), —N(R^(f))C(═O)OR^(e),—N(R^(f))C(═O)NR^(a)R^(f), —N(R^(f))C(═NR^(a))NR^(a)R,—N(R^(f))S(═O)₂R^(e), —N(R^(f))S(═O)₂NR^(a)R^(f),—NR^(f)C₂₋₆alkylNR^(a)R^(f) and —NR^(f)C₂₋₆alkylOR^(f); or,alternatively, R¹¹ and R¹² together form a -R¹¹-R¹²-bridge selected from—O—C≡C—O—, —N—C≡C—C— and —N═C—C═C—, wherein the bridge is substituted by0, 1 or 2 substituents selected from ═O, R^(e), halo, cyano, nitro,—C(═O)R^(e), —C(═O)OR^(e), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f),—OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(f))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(f), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(f))C(═O)R^(e),—S(═O)₂N(R^(f))C(═O)OR^(e), —S(═O)₂N(R^(f))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(f))C(═O)R^(e), —N(R^(f))C(═O)OR^(e),—N(R^(f))C(═O)NR^(a)R^(f), —N(R^(f))C(═NR^(a))NR^(a)R^(f),—N(R^(f))S(═O)₂R^(e), —N(R^(f))S(═O)₂NR^(a)R^(f),—NR^(f)C₂₋₁alkylNR^(a)R^(f) and —NR^(f)C₂₋₆alkylOR^(f).
 3. A compoundaccording to claim 1, wherein R¹ is


4. A compound according to claim 1, wherein R¹ is R^(b) substituted by1, 2 or 3 substituents independently selected from R⁵.
 5. A compoundaccording to claim 1, wherein R⁴ is

but in no instance is R⁴ 3,5-ditrifluoromethylphenyl or3-trifluoromethyl-4-fluorophenyl, -phenyl-(C₁₋₈alkyl),-phenyl-O—(C₁₋₆alkyl), -phenyl-NR^(a)R^(a) or-phenyl-N(R^(a))C(═O)(C₁₋₈alkyl).
 6. A compound according to claim 1,wherein R¹⁵⁴ is a saturated or unsaturated 5- or 6-membered ringheterocycle containing 1, 2 or 3 atoms selected from O, N and S that isoptionally vicinally fused with a saturated or unsaturated 3- or 4-atombridge containing 0, 1, 2 or 3 atoms selected from O, N and S with theremaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2, wherein the carbon atoms of the heterocycleand bridge are substituted by 0, 1, 2 or 3 substituents independentlyselected from R^(e), C₁₋₄haloalkyl, halo, nitro, cyano, oxo, —OR^(f),—S(═O)_(n)R^(e), —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —OC₁₋₆alkylC(═O)OR^(e), —NR^(a)R^(f),—NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(f).NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(e), —C(═O)OR^(e), —OC(═O)R^(e),—C(═O)NR^(a)R^(f) and —NR^(a)C(═O)R^(e); and unsaturated carbon atomsmay be additionally substituted by ═O; and any available nitrogen atomsin the heterocycle and bridge are substituted by H, —C 16alkylOR^(f),R^(e), —C₁₋₆alkylNR^(a)R^(f), —C₁₋₃alkylC(═O)OR^(e),—C₁₋₃alkylC(═O)NR^(a)R^(f), —C₁₋₃alkylOC(═O)R^(e),—C₁₋₃alkylNR^(a)C(═O)R^(e), —C(═O)R^(c) or —C₁₋₃alkylR^(c).
 7. Acompound according to claim 1, wherein R⁵ is independently, at eachinstance, R^(f), R^(g), halo, nitro, cyano, —OR^(e), —OR^(g),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C 16alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e),—OC(═O)NR^(a)R^(f), a phenyl ring substituted with 0, 1, 2, or 3substituents independently selected from R¹⁰; or R⁵ is a saturated orunsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atomsselected from O, N and S, substituted with 0, 1, 2, or 3 substituentsindependently selected from R¹⁰.
 8. A compound according to claim 1,wherein R⁷ is independently, at each instance, C₃₋₅alkyl orC₁₋₂haloalkyl.
 9. A compound according to claim 1, wherein R¹⁰ and R¹¹together are a saturated or unsaturated 3- or 4-atom bridge containing1, 2 or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the bridge is substituted by 0, 1 or 2 substituents selectedfrom ═O, R^(e), halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(e),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(f))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(f), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(f))C(═O)R^(e),—S(═O)₂N(R^(f))C(═O)OR^(e), —S(═O)₂N(R^(f))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(f))C(═O)R^(e), —N(R^(f))C(═O)OR^(e),—N(R^(f))C(═O)NR^(a)R^(f), —N(R^(f))C(═NR^(a))NR^(a)R^(f),—N(R^(f))S(═O)₂R^(e), —N(R^(f))S(═O)₂NR^(a)R^(f),—NR^(f)C₂₋₆alkylNR^(a)R^(f) and —NR^(f)C₂₋₆alkylOR^(f).
 10. A compoundaccording to claim 1, wherein R¹⁰ and R¹¹ together are a saturated orunsaturated 3-atom bridge containing 1, 2 or 3 atoms selected from O, Nand S with the remaining atoms being carbon, so long as the combinationof O and S atoms is not greater than 2, wherein the bridge issubstituted by 0, 1 or 2 substituents selected from ═O, R^(e), halo,cyano, nitro, —C(═O)R^(e), —C(═O)OR^(e), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(f))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(f), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(f))C(═O)R^(e), —S(═O)₂N(R^(f))C(═O)OR^(e),—S(═O)₂N(R^(f))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(f))C(═O)R^(e),—N(R^(f))C(═O)OR^(e), —N(R^(f))C(═O)NR^(a)R^(f),—N(R^(f))C(═NR^(a))NR^(a)R^(f), —N(R^(f))S(═O)₂R^(e),—N(R^(f))S(═O)₂NR^(a)R^(f), —NR^(f)C₂₋₆alkylNR^(a)R^(f) and—NR^(f)C₂₋₆alkylOR^(f).
 11. A compound according to claim 1, wherein R¹⁰and R¹¹ together are a saturated or unsaturated 3- or 4-atom bridgecontaining 1, 2 or 3 atoms selected from O, N and S with the remainingatoms being carbon, so long as the combination of O and S atoms is notgreater than 2, wherein the bridge is substituted by 1 or 2 substituentsselected from R^(e), halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(e),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(f))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(f), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(f))C(═O)R^(e),—S(═O)₂N(R^(f))C(═O)OR^(e), —S(═O)₂N(R^(f))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(f))C(═O)R^(e), —N(R^(f))C(═O)OR^(e),—N(R^(f))C(═O)NR^(a)R^(f), —N(R^(f))C(═NR^(a))NR^(a)R^(f),—N(R^(f))S(═O)₂R^(e), —N(R^(f))S(═O)₂NR^(a)R^(f),—NR^(f)C₂₋₆alkylNR^(a)R^(f) and —NR^(f)C₂₋₆alkylOR^(f).
 12. A compoundaccording to claim 1, wherein R¹¹ and R¹² together are a saturated orunsaturated 3- or 4-atom bridge containing 1, 2 or 3 atoms selected fromO, N and S with the remaining atoms being carbon, so long as thecombination of O and S atoms is not greater than 2, wherein the bridgeis substituted by 0, 1 or 2 substituents selected from ═O, R^(e), halo,cyano, nitro, —C(═O)R^(e), —C(═O)OR^(e), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(f))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(f), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(f))C(═O)R^(e), —S(═O)₂N(R^(f))C(═O)OR^(e),—S(═O)₂N(R^(f))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(f))C(═O)R^(e),—N(R^(f))C(═O)OR^(e), —N(R^(f))C(═O)NR^(a)R^(f),—N(R^(f))C(═NR^(a))NR^(a)R^(f), —N(R^(f))S(═O)₂R^(e),—N(R^(f))S(═O)₂NR^(a)R^(f), —NR^(f)C₂₋₆alkylNR^(a)R^(f) and—NR^(f)C₂₋₆alkylOR^(f).
 13. A compound according to claim 1, wherein R¹¹and R¹² together are a saturated or unsaturated 3-atom bridge containing1, 2 or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the bridge is substituted by 0, 1 or 2 substituents selectedfrom ═O, R^(e), halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(e),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR, —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(f))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(f), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(f))C(═O)R^(e),—S(═O)₂N(R^(f))C(═O)OR^(e), —S(═O)₂N(R^(f))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(f))C(═O)R^(e), —N(R^(f))C(═O)OR,—N(R^(f))C(═O)NR^(a)R^(f), —N(R^(f))C(═NR^(a))NR^(a)R^(f),—N(R^(f))S(═O)₂R^(e), —N(R^(f))S(═O)₂NR^(a)R^(f),—NR^(f)C₂₋₆alkylNR^(a)R^(f) and —NR^(f)C₂₋₆alkylOR^(f).
 14. A compoundaccording to claim 1, wherein R¹¹ and R¹² together are a saturated orunsaturated 3-atom bridge containing 1 or 2 atoms selected from O, N andS with the remaining atoms being carbon, wherein the bridge issubstituted by R^(e), C(═O)R^(e), —C(═O)OR^(e), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(f))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(f), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(f))C(═O)R^(e), —S(═O)₂N(R^(f))C(═O)OR^(e),—S(═O)₂N(R^(f))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(f))C(═O)R^(e),—N(R^(f))C(═O)OR^(e), —N(R^(f))C(═O)NR^(a)R^(f),—N(R^(f))C(═NR^(a))NR^(a)R^(f), —N(R^(f))S(═O)₂R^(e),—N(R^(f))S(═O)₂NR^(a)R^(f), —NR^(f)C₂₋₆alkylNR^(a)R^(f) or—NR^(f)C₂₋₆alkylOR^(f).
 15. A compound according to claim 1, wherein R¹¹and R¹² together are a saturated or unsaturated 3-atom bridge containing1 or 2 atoms selected from O, N and S with the remaining atoms beingcarbon, wherein the bridge is substituted by —C(═O)R^(e), —C(═O)OR^(e),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(f))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(f), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(f))C(═O)R^(e), —S(═O)₂N(R^(f))C(═O)OR^(e),—S(═O)₂N(R^(f))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(f))C(═O)R^(e),—N(R^(f))C(═O)OR^(e), —N(R^(f))C(═O)NR^(a)R^(f),—N(R^(f))C(═NR^(a))NR^(a)R^(f), —N(R^(f))S(═O)₂R^(e),—N(R^(f))S(═O)₂NR^(a)R^(f), —NR^(f)C₂₋₆alkylNR^(a)R^(f) or—NR^(f)C₂₋₆alkylOR^(f).
 16. A compound according to claim 1, wherein R³is H.
 17. A compound according to claim 1, wherein R² is H.
 18. A methodof making a compound according to claim 1, comprising the step of:reacting

with R⁴NH₂ to form


19. A pharmaceutical composition comprising a compound according toclaim 1 and a pharmaceutically-acceptable diluent or carrier.
 20. Amethod of treating acute, inflammatory and neuropathic pain, dentalpain, general headache, migraine, cluster headache, mixed-vascular andnon-vascular syndromes, tension headache, general inflammation,arthritis, rheumatic diseases, osteoarthritis, inflammatory boweldisorders, inflammatory eye disorders, inflammatory or unstable bladderdisorders, psoriasis, skin complaints with inflammatory components,chronic inflammatory conditions, inflammatory pain and associatedhyperalgesia and allodynia, neuropathic pain and associated hyperalgesiaand allodynia, diabetic neuropathy pain, causalgia, sympatheticallymaintained pain, deafferentation syndromes, asthma, epithelial tissuedamage or dysfunction, herpes simplex, disturbances of visceral motilityat respiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritis, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders, comprising the step of administering a compound according toclaim 1 to a mammal.
 21. A method of treating acute, inflammatory andneuropathic pain, dental pain, general headache, migraine, clusterheadache, mixed-vascular and non-vascular syndromes, tension headache,neuropathic pain and associated hyperalgesia and allodynia, diabeticneuropathy pain, causalgia, and sympathetically maintained pain,comprising the step of administering a compound according to claim 1.22. A method of treating acute, inflammatory and neuropathic pain,comprising the step of administering a compound according to claim 1 toa mammal.
 23. A method of treating acute, inflammatory and neuropathicpain, comprising the step of administering a compound according to claim2 to a mammal.